The natural hosts of IAV are aquatic birds, which may sporadically transmit viruses to poultry. Humans are, on occasion, infected by these viruses, causing what is known as avian influenza, which is associated with severe disease and high fatality rates 5 , 6. Uncomplicated cases of influenza are limited to attachment and viral replication in the upper respiratory tract, and the symptoms in these cases are nasal obstruction, cough, sore throat, headache, fever, chills, anorexia, and myalgia. These symptoms are the consequences of the inflammation induced upon viral infection 7.
Complications of IAV infection are more frequent in people with underlying comorbidities, such as chronic pulmonary or cardiac disease, asthma, immunosuppression, or diabetes mellitus. These complications begin when the viral infection reaches the alveolar epithelium in the lower respiratory tract, where severe tissue damage may occur and affect gas exchange. In alveolar tissue, type I pneumocytes prevent fluid leakage across the alveolar—capillary barrier, and type II pneumocytes resorb fluid from the alveolar lumen and produce lung surfactant 8. Thus, damage of the alveolar epithelium leads to respiratory dysfunction or acute respiratory distress syndrome ARDS , which often occurs in cases of severe influenza.
More extensive discussion on the contribution of the different cell types to tissue damage during influenza infection has been recently published in a very interesting review 9. Most of the lung pathology during influenza virus-induced ARDS is associated with the release of cytokines and other pro-inflammatory mediators, and the contribution of the direct viral cytopathic effect to the alveolar damage is still unclear 10 , H5N1 viruses have also been reported to spread to extra-respiratory tissue, although with limited or no viral replication Influenza complications are also frequently associated with secondary bacterial infections, which may be explained by a series of changes that the virus induces in the lung epithelial cells of the host that predisposes to adherence and invasion as well as changes in the immune response 13 — For example, it is believed that IAV infection upregulates CD receptor in lung myeloid cells, which is involved in negative immune regulation upon interaction with the ligand CD, resulting in predisposition to secondary bacterial infection Disease severity caused by IAV infection is greatly associated with high levels of inflammation, with increasing evidence that tissue damage is produced by an exaggerated innate immune response.
Thus, many researchers have proposed that treatment with anti-inflammatory therapy could be beneficial. The primary challenge to successfully establish this type of therapy is to downregulate specific mediators of the immune system that have a detrimental effect while avoiding increased levels of viral replication. Here, a review of the innate immunity processes associated with severe cases of IAV infection is provided.
Specifically, we discuss clinical studies that have been published regarding the cytokines and chemokines shown to be upregulated in serum or lung tissue of patients with severe disease. We also provide a brief review of the most frequent of those immune mediators, including signaling pathways activated by them and the cellular processes that might lead to tissue damage and disease progression.
Finally, anti-inflammatory therapies that have been proposed and tested, either in clinical, preclinical, or in vitro studies, are also discussed. The first barrier that IAV encounters when invading the host is the mucus layer covering the respiratory and oral epithelia. If the virus successfully overcomes this barrier, it can bind the respiratory epithelial cells, be internalized, and start replicating The cellular defense mechanisms that are initiated upon pathogen invasion involve the sensing of components of pathogens, or pathogen-associated molecular patterns PAMPs , by pattern-recognition receptors PRRs in host cells.
This recognition leads to activation of subsequent signaling events that result in the secretion of inflammatory cytokines, type I interferon IFN , chemokines, and antimicrobial peptides. There are several types of PRRs with a cell-type specific distribution and sub-cellular localizations that may be cytoplasmic, endosomal, or in the plasma membrane. These receptors are particularly important in the context of viral infection. Within the RLR family, the most important proteins are RIG-I, melanoma differentiation factor 5 MDA5 , and laboratory of genetics and physiology 2 LGP2 , all of which are expressed in the cytosol of most cell types and participate in the recognition of single-stranded and double-stranded RNA The most studied of the NLRs in the context of virus infection is the NLR family pyrin domain containing 3 NLRP3 , which upon stimulation leads to the activation of the inflammasome system, with important implications in inflammation NLRP3 is expressed in myeloid cell types, such as monocytes, macrophages, dendritic cells DCs , and neutrophils and in lung epithelial cells TLRs are highly expressed in antigen-presenting cells, such as DCs and macrophages, and they are also known to be expressed in several T cell subsets CLRs recognize carbohydrate ligands and are also mainly expressed in antigen-presenting cells Binding of these IFNs to their receptors in a paracrine or autocrine manner leads to the establishment of an antiviral response, characterized by the expression of hundreds of genes that will counteract viral replication Also, PAMP sensing results in the release of pro-inflammatory cytokines and chemokines by the cells that will contribute to the development and modulation of specific T cell responses and recruitment of different immune cells, such as monocytes, neutrophils, and natural killer NK cells, to the infected tissue.
In the case of antigen-presenting cells, such as DCs and some subtypes of macrophages, they also undergo maturation and migrate to the secondary lymphoid organs where antigen is presented to T 33 and B cells These adaptive immune responses initiated upon innate immune activation are known to be necessary for protection and viral clearance, as recently reviewed by Chiu and Openshaw In some cases, the virus reaches the lung, where it can infect type I and II pneumocytes, endothelial cells, and immune cells 9 , 36 — The presence of the virus is detected by infected cells, which release cytokines, chemokines, and other mediators in order to control the infection and remove dead cells and stimulate the initiation of adaptive immune responses.
However, other effects of those mediators, which are described in detail below, are detrimental for the integrity of the tissue 11 , While these alert systems are aimed to mount an effective immune response to clear viral infection, there are also important negative consequences of those responses that might compromise tissue integrity. One of the most described of those consequences is the production of ROS. Also, work by Ye et al.
In addition to reacting with DNA, proteins, and lipids resulting in structural cell and tissue damage, ROS are known to be the second messengers that participate in several signaling pathways and function as transcriptional regulators It is also known that pro-inflammatory responses activate signaling pathways that result in the activation of apoptosis and necrosis 43 , Accordingly, apoptotic alveolar epithelial cells have been observed by histochemistry of lung tissue from two patients who died by H5N1 infection Several studies have characterized the profile of cytokines in human cases of influenza in order to understand the connection between innate immunity and pathogenesis.
In cases of seasonal influenza, complications are mostly associated with secondary bacterial infection. Most cases of severe primary viral pneumonia have been associated with pandemic influenza, such as H1N1 or H1N1 influenza virus, and cases of avian influenza, such as infections by H5N1 or H7N9 influenza viruses 45 , Acute respiratory distress syndrome is the main cause of death in IAV-infected patients 47 , Histopathology caused by complicated IAV infection in the absence of bacterial pneumonia consists of inflammation, congestion, epithelial necrosis of the larger airways, and diffuse alveolar damage characterized by hyaline membranes, interstitial and intra-alveolar edema, necrotizing bronchitis and bronchiolitis, and in some cases, hemorrhage 49 , Autopsies from fatal cases of H1N1, H5N1, and the H1N1 pandemic virus show comparable pathological characteristics 47 , Fatal infection with H7N9 influenza viruses in humans also showed diffuse alveolar damage as one of the main histopathology findings The majority of the patients infected by pandemic H1N1 virus experienced a mild disease with influenza-like symptoms that typically resolved in a few weeks 47 , However, due to the lack of pre-existing immunity against this virus, complications of the disease occurred in some patients, mostly those with underlying conditions Gao et al.
In this work, they also found high levels of apoptosis in the lungs and airway by terminal deoxynucleotidyl transferase dUTP nick end labeling TUNEL staining, as well as marked levels of cleaved caspase 3 A similar study by To et al. Other studies reporting similar results are summarized in Table 1 54 , 57 , Table 1.
Cytokines and chemokines detected in serum or lung tissue samples of human subjects with severe disease infected by IAV. Cytokine responses in H5N1-infected patients have also been studied. Peiris et al. Similarly, de Jong et al. Interestingly, in both studies, they found large numbers of macrophages infiltrated in the lung, in accordance with the functions of those chemokines. The level of cytokines was associated with elevated levels of viral replication. However, the patient who did not show cytokine expression was pregnant and treatment with glucocorticoids was provided in both cases, which may have affected the immune response although it is unclear how these or other factors could have affected the results Information regarding H7N9 IAV infections in humans is more limited given the recentness of the outbreak.
Most of these studies with human samples point to elevated levels of cytokines and chemokines in IAV-infected patients. Interestingly, there is a clear overlap in the cytokines that are observed in most of those studies. A summary of the cytokines and chemokines found to be upregulated in humans infected by IAV is provided in Table 1. Since the reported data indicate that the induction of these molecules might be associated with pathogenesis, understanding the effects of those proteins in receptor-expressing cells and the signaling pathways that they induce is important for eventually translating that information to the identification of efficient and safe treatment alternatives.
Therefore, in the next section, we focus on the functions of each one of those cytokines and chemokines in more detail, as well as their participation in tissue damage in other diseases or other models as an additional indicator of their pathogenic potential. Upon influenza infection, viral PAMPs are sensed by the cells and multiple signaling pathways are activated as a part of the innate immune response. The purpose of the innate immune response is to lead to the clearance of viruses and infected cells, as well as the activation of the adaptive immune response.
However, these events can also result in tissue destruction as a consequence of excessive activation. Data discussed in the previous section indicate an association between the activation of the innate immune response, typically measured as the production of cytokines and chemokines in serum, and a more severe pathogenesis or fatality in many cases, supporting the hypothesis of causative relationship between innate immunity and severe disease. To provide deeper insights into these events and their connection, in this section we will review the effects and signaling pathways associated with the production of the main cytokines upregulated during influenza infection.
Because of the broad and numerous functions of these cytokines, it is a challenging task to parse their functions as many of them are redundant and regulated by complex networks involving multiple transcription factors, adaptors, or secondary mediators. In terms of their potential as therapeutic targets, some therapies using monoclonal antibodies to neutralize the damaging effects of those proteins have been developed and are already in the clinic for treatment of anti-inflammatory diseases, while other approaches, such as administration of pro-inflammatory cytokines, small molecules, siRNA or shRNA, or gene therapy, are under study Therefore, in this review, we provide a general overview of these processes and the related outcomes in terms of tissue damage and pathogenesis.
These events then result in caspase 3 activation and induction of apoptosis. Mice treated with one of these agents, etanercept, showed reduced lung inflammation and morbidity after challenge with influenza virus IL6 has been attributed to both pro-inflammatory and anti-inflammatory effects 82 , In addition, IL6 is involved in the regulation of metabolism, bone homeostasis, and neural processes.
The production of IL6 is tightly regulated, and its continuous production has been associated with numerous chronic and autoimmune diseases. Activation of IL6 signaling may take place through classic or trans-signaling pathways. IL6R is expressed in a limited number of cells types, namely macrophages, neutrophils, some types of T-cells, and hepatocytes However, gp is ubiquitously expressed, allowing IL6 signaling to take place in a broad range of tissues. It is believed that trans-signaling accounts for the pro-inflammatory effects of IL6, while the classic signaling is more associated with anti-inflammatory effects.
A very interesting review by Scheller et al. Dimerization of gp leads to Janus kinases JAK activation, which results in phosphorylation of tyrosine residues in the cytoplasmic region of gp Next, the signal transducer and activator of transcription STAT 3 is phosphorylated, dimerizes, and translocates to the nucleus to regulate the expression of multiple genes associated with the induction of cell growth, differentiation, and survival IL6 can also lead to the activation of phosphatidylinositol-4,5-bisphosphate 3-kinase PI3K 87 , which is classically associated with survival and cell growth.
Acute phase proteins are secreted mainly by hepatocytes, and have multiple immunomodulatory effects. They are structurally and chemically unrelated, and there is a broad amplitude in their physiological functions, which ranges from inhibition of pathogen growth, facilitation of their removal by phagocytic cells, and elimination of infected cells to other unrelated functions, such as providing anti-inflammatory feedback to the immune system or modulation of coagulation CRP is perhaps the most studied of these proteins, and it is frequently used as a diagnostic marker for inflammation.
Interestingly, CRP is known to be released locally by cells of the respiratory epithelia and the liver in response to cytokine stimulation and that patients with ARDS have high levels of CRP CRP was identified as a biomarker of disease severity in patients hospitalized with IAV infection at the time of admission However, another study indicates that, although the levels of CRP are elevated in patients with acute lung injury, a higher level of plasma CRP predicts a more favorable outcome in adult patients This protein has both pro-inflammatory and anti-inflammatory functions, and its function remains to be well characterized.
Chronic overexpression of these acute phase proteins is also characteristic of some chronic, autoimmune pro-inflammatory diseases, such as RA.
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Excessive production of IL6 has been associated with several pathological manifestations, such as Castleman disease or RA. For this reason, IL6 has been extensively investigated as a therapeutic target, leading to the development of monoclonal antibodies, such as tocilizumab, which has already been approved for the treatment of these diseases However, in the case of IAV infection, IL6 seems to have a protective role in the mouse model, promoting viral clearance and limiting inflammation 95 , indicating that IL6 blocking agents might not be adequate for inflammation treatment during IAV infection.
This latter property promotes the infiltration of inflammatory cells into the extravascular space IL1 cytokines are highly associated with acute and chronic inflammatory afflictions. As such, therapies to counteract the effect of this cytokine have been developed and are under study. In particular, treatment with an IL1R antagonist IL1Ra , known under the generic name anakinra, has been approved to relieve symptoms and pain in patients with RA, and it is a standard therapy for autoimmune syndromes in general 96 , Interestingly, another study showed a positive effect on survival after administrating the IL1Ra to influenza virus-infected mice The most important function of type I and type III IFN is to induce the activation of an antiviral state in infected and neighboring cells.
For this reason, these cytokines are very important for protecting against acute viral infections. In addition, type I IFNs have also an important role in the stimulation of adaptive immunity , This complex binds specific sequences in the DNA and promotes transcription of hundreds of ISGs, which leads to numerous changes in the transcriptome of the cell thus activating the antiviral response , Also, under certain conditions, type I IFNs are able to induce the formation and phosphorylation of STAT1 homodimers, which may bind gamma-activated sequences GAS and induce the expression of a different set of genes Therefore, the biological responses induced by type I and type III IFNs are very similar and mainly characterized by the induction of antiviral responses with the main difference between them being the expression of the receptor in different cell types While type I IFN is known to be a key mediator of virus clearance during influenza virus infection , excessive IFN signaling has detrimental effects on disease severity, mostly as a result of overall increased inflammation pro-inflammatory cytokines and lung-infiltrating cells , cell death, and oxidative stress that might have damaging effects on the host , The production of type I IFN and its pathological effects are supported by its role in other immune diseases.
In particular, genetic and transcriptomic analysis of blood from systemic lupus erythematosus SLE patients, has attributed type I IFN a central role in the pathogenesis of this disease Interestingly, type I IFN also has been associated with endothelial dysfunction through induction of endothelial nitric oxide synthase However, the mechanisms of type I IFN-mediated regulation of oxidative stress have not been analyzed in detail.
While the damaging potential of type I IFN is evident, the main feature of this family of cytokines is that they are crucial inducers of the antiviral response and therefore they are absolutely required to fight IAV infection. Studies performed in mice clearly indicate that viral replication and disease severity are increased in the absence of IFN, indicating that both type I and type III IFN having protective roles Given the importance of type I IFN induction in defeating viral infection at the cellular level, desirable anti-inflammatory therapies to treat IAV or other viral infections should not fully blunt this type of response.
Type II IFN plays important roles in the stimulation of antigen presentation by macrophages, in activating the cellular Th1 responses upon infection by intracellular pathogens, and in regulating B cell functions A very important consequence of the activation of macrophages and neutrophils by IFN is the enhancement of microbial killing processes, mainly mediated by induction of the NADPH-dependent phagocyte oxidase system or respiratory burst release of ROS , stimulation of NO production, and upregulation of lysosomal enzymes , This defense mechanism, however, is also damaging for infected tissues and has been shown to enhance the pathogenesis during IAV infections 41 , Chemokines are small chemotactic cytokines that play important roles in driving many components of inflammation, the most important of which is leukocyte migration.
Chemokine receptors in the cell surface are transmembrane G protein-coupled receptors GPCRs , and their activation leads to the transduction of intracellular signaling pathways that promote migration toward the chemokine source. Other functions mediated by chemokines include regulation of cell viability, proliferation, differentiation, and migration The chemokine system is very promiscuous in providing flexibility and specificity in the trafficking of immune cells, and a specific chemokine may act on several leukocyte populations to coordinate the recruitment of cells with related functions.
In particular, it has been shown to induce the migration and recruitment of T cells, DCs, macrophages, monocytes, eosinophils, NK cells, mast cells, and basophils — Also, it induces the proliferation and activation of certain NK cells. Interestingly, RANTES is a co-receptor for HIV and for this reason, there is a field of intensive research to develop pharmacological inhibitors of this receptor with the ultimate goal of producing a therapeutic agent , High levels of RANTES have also been associated with extensive inflammation of the lung in cases of avian influenza and other viral infections.
Several cell types release IP10, including T lymphocytes, neutrophils, monocytes, DCs, endothelial and epithelial cells, and fibroblasts. As a consequence of this interaction, signal transduction leads to chemotaxis toward inflamed or infected areas, apoptosis, and proliferation or cell growth inhibition IP10 is known to contribute to the pathogenesis of several infectious diseases and of many autoimmune diseases, such as type 1 diabetes, RA, psoriatic arthritis, or SLE Experiments in mice have shown that the lack of IP10 or its receptor reduces the severity of ARDS during influenza virus infection, suggesting the potential of this signaling pathway as a therapeutic target for ARDS treatment This chemokine is mainly produced by macrophages, epithelial cells, and endothelial cells Interestingly, monocytes and macrophages produce low amounts of IL8 during influenza virus infection , while epithelial cells produce high levels of IL8 in vitro Several transcription factors activated upon viral recognition have been shown to bind IL8 promoter and stimulate IL8 production.
IL8 has a significant role in ARDS, which is characterized by a large influx of neutrophils to the lung during severe influenza Neutrophils protect against microbial infection through the release numerous factors such as ROS, proteinases, and neutrophil extracellular traps, molecules that, when produced in excess, might also have damaging effects In addition to the contribution of IL8 to pathogenesis through increased inflammation via neutrophil recruitment, patients with ARDS also have been shown to present auto-IL8 antibodies that complex with IL8. MCP1 or CCL2 regulates the migration and infiltration of cells expressing the receptor CCR2, which includes monocytes, memory T lymphocytes, and NK cells, and is produced either constitutively or after induction by oxidative stress or pro-inflammatory mediators.
It also participates in the phenotypic polarization of memory T cells toward a Th2 phenotype , MCP1 is produced by several different cell types, including endothelial, fibroblast, epithelial, smooth muscle, and monocyte cells among others, monocyte and macrophages being the main sources This chemokine has been implicated in the pathogenesis of several diseases, such as asthma , RA, cardiovascular diseases, cancer , and some neuropathologies On the one hand, one study showed that neutralization of MCP1 in vivo reduced the immunopathology in a mouse model However, a different report showed increased alveolar epithelial damage and apoptosis upon a similar treatment Thus, further characterization on the role of this chemokine is necessary to determine its potential as a target for anti-inflammatory therapy.
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It also induces activation of these cells and increased adhesion Low levels are constitutively expressed but its production is activated by multiple inducers such as PAMPs and cytokines in different cell types, including monocytes, macrophages, neutrophils, DCs, epithelial cells, fibroblast, and multiple cells from the nervous system As described above, the current literature indicates a clear role for hypercytokinemia during severe IAV infection.
Initially, cytokine production is induced following detection of the virus by cellular PRRs Figure 1. Therefore, the primary treatment of IAV infection should be antiviral compounds, such as neuraminidase inhibitors, which will limit viral replication and spread, and therefore minimize the production of pro-inflammatory cytokines.
Inflammation results in the induction of multiple cellular processes that lead to increased oxidative stress, apoptosis, necrosis, altered adhesion, and migration of immune cells to the lung. In addition, these processes lead to the release of additional secondary mediators and induction of cytokines, which results in amplified inflammation leading to increased damage Figure 1.
Therefore, it is worth considering therapies that modulate these detrimental processes in combination with antiviral agents. Targeting some of the most prevalent cytokines or related signaling pathways in severe influenza in mouse models, using either knock out animals or blocking agents, have been shown to reduce lung damage and mortality in multiple studies as indicated in the previous section, supporting the idea that anti-inflammatory agents inhibiting the same pathways could be beneficial in humans.
One of the most important parameters that should be evaluated among these anti-inflammatory agents is that the treatment should reduce the negative effects of inflammation but not the innate and adaptive immune arms that are responsible for restricting viral replication and spread.
However, the pathways initiated by the most prevalent cytokines are very redundant and dissecting these complex responses is very challenging. Inhibition of specific chemokines or their receptors are also possible strategies. A few reports have been reported evaluating the consequence of blocking their function, which indicated that IP10 and MCP1 might have beneficial effects on reducing morbidity due to inflammation, while deficiency in RANTES expression seems to be detrimental.
Further studies in animal models should be performed to better understand which of these pathways could be targeted as an anti-inflammatory therapy during severe influenza disease. In addition to cytokines and chemokines, other elements of the inflammatory response are under consideration for this purpose. In this section, we review those therapies that have been evaluated in the clinic or that have shown promising results in preclinical studies, such as broad-spectrum therapies, other signaling mediators or their receptors, or molecules involved in the generation of oxidative stress.
Figure 1. Activation of innate immune processes by IAV and therapeutic opportunities to modulate the immune response. When IAV invades a new host, it infects and replicates in cells of the respiratory tract. The development of the inflammatory response is accompanied by multiple changes in gene expression that also result in damage of the infected tissue. Antiviral treatment is the first opportunity to reduce viral load and inflammation indicated in green, left panel.
The use of anti-inflammatory drugs to reduce cytokine- and chemokine-induced damage that could be used in combination with antiviral therapies is under investigation indicated in green, right panel. Corticosteroid treatment has been proven to be safe in patients with ARDS and is associated with reduced inflammation and improved clinical status For this reason, the use of these drugs has been considered for the treatment of severe influenza and has, in fact, been used in several cases of avian influenza H5N1 virus infection In addition, corticosteroids are regularly used in long-term treatment for asthma and chronic obstructive pulmonary disease COPD.
Thus, understanding the effect of these drugs during influenza virus infection is very relevant not only for their anti-inflammatory use in cases of IAV infection but also to determine the best methods to manage these high risk patients in the clinical setting. Several studies have evaluated the consequences of using corticosteroids in humans with influenza infection, with varying results. A study by Quispe—Laime reported a reduction in lung injury and multiple organ dysfunctions in H1N1 influenza virus-infected patients treated with corticosteroids However, as recently reviewed by Hui and Lee, several clinical trials indicate that the administration of these steroids during influenza virus infection, either in the presence or absence of neuraminidase inhibitors, has either no effect or even a detrimental effect A retrospective study by Kudo and colleagues evaluated the effect of corticosteroid administration in patients with H1N1 IAV infection with pneumonia and did not find a negative effect of the steroid treatment On the other hand, Lee et al.
Accordingly, another retrospective study in adults infected with H1N1 influenza virus showed an association of corticosteroid treatment with increased mortality An interesting study by Thomas et al. Similarly, an in vivo experiment in the same study showed higher replication in a mouse model after treatment, which resulted in enhanced inflammation. This is in agreement with the recent meta-analysis of the literature performed by Zhang et al.
Consequently, the current literature suggests that the corticosteroid treatment is not a good choice for the treatment of acute inflammation during influenza virus infection, probably due to increased viral replication as a consequence of reduced antiviral responses Accordingly, WHO discourage the use of corticosteroid drugs as routine treatment for severe influenza due to the paucity of evidence for beneficial effects Further research in this field should be done, given the routine use of chronic corticosteroids treatment in some other medical conditions, such as asthma and COPD, both of which are considered high risk populations for influenza disease.
Statins are also a class of drugs with extensive use in the clinic given their ability to decrease cholesterol levels, thus reducing the risk of cardiovascular disease. These drugs are inhibitors of the hydroxyl methylglutaryl-coenzyme A HMG-CoA reductase enzyme, acting in the cholesterol synthesis pathway. Interestingly, these drugs also have anti-inflammatory properties , which have been analyzed in the context of influenza infection By altering the cholesterol synthesis route, statins also reduce the synthesis of lipid intermediates necessary for isoprenylation of multiple proteins.
Consequently, multiple intracellular signaling pathways activated during the development of the inflammatory response are also affected An observational study that included more than patients hospitalized with influenza in the United States identified an association of statin use with reduced mortality Other clinical studies have also shown that statin use could be beneficial in the treatment of influenza , , while yet other studies did not find supporting evidence for the use of this type of drug , These retrospective studies, however, have the limitation that patients who are prescribed statins are some of those who are already at a higher risk for developing severe disease due to pre-existing cardiovascular disease and timing, duration and dose of the statin treatments are difficult to control.
An interesting review by Mehrbod et al. While the literature on this topic shows varied results, there is increasing evidence for a possible beneficial effect of the use of statins during influenza treatment, and further experimentation to confirm a positive effect should be developed. This is supported by several in vitro and in vivo studies that have indicated that, in addition to diminishing the production of cytokines upon influenza virus infection, statins also seem to result in decreased levels of viral replication — N -acetylcysteine is also a commonly used compound, which is mainly known for its mucolytic as well as anti-oxidant properties.
Interestingly, anti-inflammatory properties have been also attributed to this molecule, which are probably associated with its anti-oxidant function by diminishing oxidative stress during inflammation. Related to this, animal models of systemic endotoxin-induced shock or acute lung injury showed reduced production of cytokines and tissue damage upon treatment with N-acetylcysteine — Although the effect of this molecule in the context of influenza treatment has not been broadly studied, there are some reports indicating a possible beneficial effect.
One study by Geiler et al. Data from in vivo studies also seem to indicate that N -acetylcysteine might help to protect against IAV-induced pathology It is important to note that in this case, contradictory reports have also been published, such as the study by Garigliany and Desmecht, which did not find an effect of the treatment in the mouse model In humans, de Flora et al. Therefore, although the amount of data reported is scarce, there seems to be evidence for a possible safe and beneficial effect for the use of N -acetylcysteine to treat inflammation by influenza without enhancing viral replication.
However, studies evaluating this molecule in humans are very limited, and more extensive work is needed to obtain conclusive information. Macrolides, which are generally used for their antibacterial activity, also have immunomodulatory properties. The ability of macrolides to interfere with multiple signaling pathways accounts for these immunomodulatory properties.
In vitro studies have shown that clarithromycin clearly reduces viral replication in epithelial cell lines approximately 4—7 h after viral adsorption This effect is therefore also independent of the anti-inflammatory activity and might be mediated by alteration in cell signaling pathways.
In vivo studies also support a potential role for the macrolides in improving recovery upon infection with IAV In the clinic, macrolides are sometimes administered in cases of influenza to treat secondary bacterial infections and because of their anti-inflammatory effects, clarithromycin being the most frequently prescribed first-line drug Higashi et al.
Their data indicated a possible effect in reducing fever, but they did not observe any differences in IL6 serum levels. However, another study could not find any association between significant improvement of symptoms and the use of macrolides. In general, the number of studies evaluating macrolides in IAV infection is very limited.
While in vitro and in vivo data showed promising results as indicated by a reduction of pro-inflammatory molecules alongside reduced viral replication, the small number of clinical studies does not suggest a significant benefit. Also, the use of antibiotics should be limited to cases with secondary bacterial infections, given the risk for emerging resistances.
In addition, mice studies have shown that treatment with a combination of several antibiotics leads to impaired innate and adaptive immune responses and delayed virus clearance as a consequence of changes in the respiratory microbiota , and therefore its use during influenza virus infection in humans should be further analyzed and cautiously used during severe infections. Cyclooxygenase enzymes catalyze the conversion of arachidonic acid to prostaglandins, which play important roles in modulating immune responses and inflammation.
Importantly, COX enzymes are main targets for non-steroidal anti-inflammatory drugs including aspirin, ibuprofen, diclofenac, naproxen, and for selective COX-2 inhibitors, such as celecoxib and nimesulide, and are therefore very available and frequently used as treatment for other conditions. Considering the well-described pro-inflammatory role of COX-2, studies to understand its function in influenza pathogenesis have been performed. COX-2 knock out mice infected with IAV showed reduced levels of pro-inflammatory cytokines and mortality, but also increased levels of replication Interestingly, COX-1 ablation showed opposite results, with augmented and earlier inflammatory responses.
In vitro experiments have shown that COX-2 inhibitors play a regulatory role in mediating pro-inflammatory responses after H5N1 infection , and have been shown to have a direct antiviral effect in human macrophages infected with H5N1 influenza virus However, another in vivo study did not find a beneficial effect from celecoxib treatment in mice infected with an H3N2 virus. Therefore, data regarding COX-2 inhibitors are also controversial. Another in vivo study did observe a positive effect of celecoxib administration when used in combination with mesalazine or 5-aminosalicylic acid another anti-inflammatory drug in addition to a neuraminidase inhibitor in mice challenged with H5N1 IAV , supporting the idea that a combination treatment might be more efficient.
To date, there are no systematic human studies evaluating COX-2 inhibitors for influenza treatment. The event that these studies move forward is important to consider the selectivity for COX-2 inhibitors, since COX-1 inhibitors would have an opposite effect, increasing inflammation, and pathogenesis. Indeed, an increased risk of mortality during influenza virus infection was associated with aspirin, paracetamol, and diclofenac in animal models in a meta-analysis of the literature Peroxisome proliferator-activated receptors PPAR are nuclear receptors and ligand-activated transcription factors that control a number of target genes upon assembly of a transcriptional complex.
There are several PPAR, but in general, they are regulators of energy balance, including glucose homeostasis, fatty acid oxidation, and lipid metabolism, and are frequently used in the treatment of diabetes Several in vivo studies point to a possible benefit of the use of these drugs in treating influenza infection. Moseley at al. While these drugs have not been thoroughly studied for influenza treatment and no human studies have been performed so far, exploring their potential would be of great interest given their current use in the clinic and availability, which would facilitate their study in clinical trials Sphingosinephosphate S1P is a lipid signaling mediator synthesized from ceramides.
The laboratory of Dr. They were first able to demonstrate that the administration of a promiscuous S1P receptor agonist led to a significant reduction of cytokines and chemokines upon influenza infection in the mouse model — This reduction of the inflammatory response correlated with a decrease in lung injury and improved survival upon infection Importantly, the reduction of inflammation was not accompanied by a delayed clearance of the virus, indicating a potential for the use of these drugs as a therapeutic agent Further work using S1PR agonists led them to describe a central role for endothelial cells in the generation of the cytokine storm They further searched for the signaling pathways that the S1PR agonists might use to exert these anti-inflammatory-protective functions during IAV infection and found that the effect observed is independent of TLR3, TLR7, or cytosolic signaling pathways Therefore, although S1PR agonists are under investigation in mice and ferrets for influenza treatment , results from these studies are promising as a possible future treatment for hypercytokinemia in severe cases of influenza.
One S1PR agonist has been approved in the clinic by the FDA for the treatment of relapsing—remitting multiple sclerosis. However, adverse effects have been noted in the use of this drug, and the safety profile of this and other S1PR agonists should be further investigated Platelet-Activating Factor PAF is a phospholipid mediator involved in many cellular processes including cell motility and synthesis of cytokines and other signaling mediators It is known that expression of PAFR in the airway is upregulated by IAV infection, and it is believed that this facilitates bacterial adherence and therefore susceptibility to Streptococcus pneumonia The use of PAFR antagonists has been proposed in different pathological settings, including influenza, mainly due to their anti-inflammatory properties This overall reduced immune response did not result in an elevated level of viral replication.
While according to these data, PAFR antagonists could be candidates to treat inflammation during influenza, further characterization of the effect of these drugs should be performed. Other anti-inflammatory therapies have been tested in animal models resulting in reduced inflammation, morbidity, and mortality. While these studies support the potential positive effect of immunomodulatory therapy in severe influenza, the scientific data in this field are very preliminary, and extensive investigation is needed to develop these treatments for human use.
Here we discuss some of these treatments. There is evidence that activation of NOX2 promotes lung oxidative stress, inflammation, injury, and dysfunction resulting from infection with IAV ranging from low to high pathogenicities Apocynin, a NOX2 inhibitor, inhibited influenza-induced hypercytokinemia and ROS production in airway epithelial and immune cells in vitro , while not affecting viral replication A study by Sharma et al.
This study showed a clear reduction in the levels of cytokines and chemokines, lung infiltration, alveolitis, and overall lower mortality in H1N1-infected mice, all while not affecting the levels of viral replication Another research group further explored the combination of antiviral and anti-inflammatory therapy and generated a novel compound with these two properties by conjugating two drugs, zanamivir a neuraminidase inhibitor and caffeic acid cytokine suppressor There is substantial information in the literature supporting the association of influenza pathogenesis with high levels of inflammation and production of cytokines and chemokines, highlighting the opportunity to identify immunomodulatory drugs that could reduce the inflammation-associated damage in the lung seen in severe cases of influenza.
These therapies should be evaluated in combination with antivirals, which control virus replication and spread. Reduction of viral load with antiviral drugs also acts to decrease inflammation by lowering the presence of PAMPs to be sensed by cellular PRRs. In addition, one crucial aspect to assess when testing these drugs is to assure that the treatment does not provide an environment for enhanced replication due to a general shutdown of the innate and adaptive immunity.
To date, the therapies studied in humans have commonly used broad-spectrum anti-inflammatory drugs, which are frequently used for other affections. Corticosteroids are a good example of those therapies, which are frequently used in patients with asthma and COPD, and have been evaluated in multiple studies with conflicting results. Some of those studies point to a possible detrimental role of treatment with corticosteroids, and their use should be avoided if possible until their effect is better understood.
Other broad-spectrum anti-inflammatory drugs that could be beneficial are statins, N -acetylcysteine, and COX-2 inhibitors. However, there is no sufficient data in the current literature to justify their use. As for the last examples, targeting cell surface receptors in immune cells is an attractive approach since this would facilitate cellular accessibility of the drug. Further research to bring these therapies closer to the clinic in the context of IAV infection is needed, as well as for the identification of novel immunomodulatory agents.
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. We thank Anthony C. Fredericks for kindly reviewing the manuscript. Google Scholar. Estimates of deaths associated with seasonal influenza — United States, PubMed Abstract Google Scholar.
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CXCL12 is the most potent angiogenic chemokine. Other CXC chemokines have also been implicated in angiogenesis. Chemokines can affect angiogenesis via binding to chemokine receptors expressed on endothelial cells, leading to increased migration and in some cases proliferation and the inhibition of apoptosis Chemokines can work in concert with other angiogenic factors to promote angiogenesis Furthermore, chemokines can attract angiogenic factor-producing leukocytes, such as macrophages, into the TME, accelerating angiogenesis As mentioned above, chemokines are also capable of inhibiting angiogenesis.
These effects have been shown to be mediated by the ability of CXCL4 and CXCL10 to displace basic endothelial growth factors from their required heparan sulfate proteoglycan coreceptors 23 - Metastasis refers to the process during which malignant tumor cells spread from the site of the primary tumor to distant sites of the body and is the leading cause of death for most solid tumors.
A number of studies have found that chemokines play an integral role in metastasis. Tumor cells express selected chemokine receptors, which can help direct tumor cells to specific anatomic sites to form metastases Its involvement in metastasis has also been demonstrated in different types of tumors, such as prostate cancer, lung cancer and glioblastoma In human patients, expression of CXCR4 is correlated with increased tumor metastasis 30 - The entry of tumor cells into lymphatic vessels is critical for the development of metastasis, and CCR7 and its ligand CCL21 are critical for this process for dendritic cells DC and T cells and may also play a similar role for tumor cells In addition to their intrinsic cellular alterations that allow unchecked proliferation, tumor cells interact with their surroundings to form and sustain a favorable TME by promoting angiogenesis, inflammation, and metastasis as well as modulating the systemic immune response.
Most, if not all, solid tumors have dominant infiltration of immune cells. Chemokines play an important role in leukocyte infiltration into any tissue, including tumors. Hence, they have a critical role shaping the immune cell composition in the TME, which affects tumor development. To eradicate a tumor, effector cells must migrate into the TME, and the presence of effector cells within a tumor can be a positive prognostic indicator. The quality of the Th1-biased immune response is an important determinant of an effective protective antitumor cellular immune response In addition, an important role of CXCR3 in macrophage polarization was found recently In a murine model of breast cancer, CXCR3 deficiency results in the polarization of macrophages towards an M2 phenotype, which has a role in promoting tumor growth; this result indicates a requirement of CXCR3 for M1 macrophage generation.
Macrophages can be polarized into M1 or M2 subtypes, depending on the activation signals they receive from their local cytokine milieu M1 macrophages exhibit tumoricidal activity and may function as antigen-presenting cells APC to activate effector T cells. In contrast, M2 macrophages promote Th2 cell responses and express high level of IL10 and pro-tumorigenic factors that facilitate growth of tumors and metastases. Paradoxically, different immune cell subsets can suppress the function of effector cells and allow tumor growth, such as tumor-associated macrophages TAM , myeloid-derived suppressor cells MDSC , and regulatory T cells Treg To gain a growth advantage, tumors can alter the local chemokine expression profile to recruit these suppressive cells.
Tregs are frequently present in tumors. Selective depletion of Tregs in various experimental and spontaneous tumor models has been shown to potently induce NK cell- and T cell-dependent antitumor immunity 47 - 50 , and the presence of Tregs in cancer patients is associated with a poor prognosis Of note, it has been demonstrated that Tregs can coexpress Th-specific transcription factors and chemokine receptors to ensure appropriate specific control of pro-inflammatory effector Th cell responses.
For tumors to escape from the host protective immunity, which is largely Th1-dependent, it is possible that tumor cells instruct Tregs to express T-bet and CXCR3 in order to suppress Th1-specific immune responses.
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They can be distinguished by the expression of different surface markers. Furthermore, they can increase the infiltration of Tregs into tumor bed via releasing different chemokines 59 , Standard first line cancer therapies, such as chemotherapy and radiotherapy, have been demonstrated to, at least partially, rely on their immunostimulatory effects for their therapeutic efficacy It has been suggested that the specific immune contexture of a tumor can be correlated to clinical outcomes Thus, the presence of specific chemokines in the TME may be a determinant of therapeutic efficacy.
In a murine transplantable tumor model of fibrosarcoma, anthracycline treatment induces the expression of CCL2 in tumor-bearing mice These cells act locally as APCs to stimulate the effector T-cell response. In melanoma, chemotherapy can also induce intratumoral expression of CXCR3 ligands and CCL5, which are important for effector T-cell trafficking into the tumor bed There is a positive correlation between the expression of these chemokines and clinical outcome. CXCL10 is also associated with the response to radiotherapy Depletion of these cells abrogated the antitumor effect of radiotherapy.
Despite the beneficial effects of chemokines that are induced by chemotherapy, chemokines can also contribute to drug resistance thereby increasing tumor cell survival. For example, in a breast cancer model, chemotherapy with doxorubucin and cyclophosphamide directly kills tumor cells As a result, there is an increased recruitment of myeloid suppressor cells in the TME, which are linked to enhanced tumor survival and metastasis.
Immunotherapy for cancer has come a long way and has just entered a golden age as a result of recent breakthroughs with checkpoint blockade therapies. Immunotherapy targeting T-cell checkpoint molecules, such as CTLA-4 and PD-1, is currently one of the most promising new therapeutic approaches for cancer therapy.
Adoptive transfer of in vitro expanded autologous T cells or genetically engineered T cells have also been showing clinical promise However, a major obstacle to obtain the maximal therapeutic effect from immunotherapy is the limitation of infiltration of effector T cells into tumor bed due to abnormal tumor vessels, hypoxic conditions and an overall suppressive microenvironment Finding ways to enhance effector T-cell trafficking and fitness has become a major goal in the field since the successful application of immunotherapy in the clinic.
Recently it has been shown that anti-PD-1 immunotherapy can enhance the therapeutic efficacy of adoptive cell-transfer therapy by increasing CXCL10 expression in the tumor The aforementioned findings demonstrate the complex role of chemokines in tumor formation and growth. Since cancer type, disease stage as well as intratumor immune cell composition affect the outcome of treatment, great care should be taken when developing chemokine-based therapies for cancer.
To date, several strategies have been developed to block chemokine-dependent responses by depleting chemokines and antagonizing their receptor signaling pathways or to augment chemokine-induced effects by increasing the expression of chemokines using different methods, such as naked DNA plasmids, engineered tumor cells and transduced DCs Lack of proper host response in the recognition of immunogenic tumors has remained one of the key challenges in the development of a reliable cancer therapy.
Immune recognition of tumor cells can only occur in the presence of APCs and lymphocytes. Hence, there has been great interest in recognizing the chemokine signals that facilitate immune-cell recruitment into tumors, ultimately with the aim of exploring the potential specific enhancement of APC and effector T-cell infiltration and blockade of Treg migration and function.
Chemokines are multifunctional mediators that not only affect immune-cell infiltration into tumors, but also have a great impact on the process of tumor growth, angiogenesis and metastasis. Contribution of chemokines to the overall outcome of tumor development depends on the balance between tumor-promoting and tumor-inhibiting factors. It has become increasingly evident that chemokines are potentially bi-functional during tumor development and may display both tumor-promoting and tumor-suppressive capabilities.
Therefore, further study of the distinctions between the pro-tumor and antitumor activities of chemokines is warranted in order to develop more effective therapies against cancer. Although the mouse tumor studies are encouraging, there is still a long way to go for utilizing chemokine-targeted therapy for the treatment of cancer patients.
Chemokines mediate the host response to cancer by directing the trafficking of leukocytes into the tumor microenvironment. This migratory response is complex and consists of diverse leukocyte subsets with both antitumor and protumor activities. Although chemokines were initially appreciated as important mediators of immune cell migration, we now know that they also play important roles in the biology of nonimmune cells important for tumor growth and progression.
The snippet could not be located in the article text. This may be because the snippet appears in a figure legend, contains special characters or spans different sections of the article. Cancer Immunol Res. Author manuscript; available in PMC Dec 1. PMID: Melvyn T. Chow and Andrew D. Address correspondence to: Andrew D. Other authors ude. Copyright notice. The publisher's final edited version of this article is available free at Cancer Immunol Res. See other articles in PMC that cite the published article. Abstract Chemokines are chemotactic cytokines that control the migration of cells between tissues and the positioning and interactions of cells within tissue.
Introduction The directed movement of cells is tightly regulated by the spatial and temporal expression of chemokines 1. Angiogenesis Cancer cells within a tumor rely on blood vessels to acquire adequate oxygen and nutrients as well as to eliminate waste 4 , Metastasis Metastasis refers to the process during which malignant tumor cells spread from the site of the primary tumor to distant sites of the body and is the leading cause of death for most solid tumors. Chemokines in tumor immunology In addition to their intrinsic cellular alterations that allow unchecked proliferation, tumor cells interact with their surroundings to form and sustain a favorable TME by promoting angiogenesis, inflammation, and metastasis as well as modulating the systemic immune response.
Chemokines in cancer therapy Standard first line cancer therapies, such as chemotherapy and radiotherapy, have been demonstrated to, at least partially, rely on their immunostimulatory effects for their therapeutic efficacy Concluding remarks Chemokines are multifunctional mediators that not only affect immune-cell infiltration into tumors, but also have a great impact on the process of tumor growth, angiogenesis and metastasis.
Open in a separate window. Figure 1. Multifaceted roles of chemokines in tumor development 1 Chemokines produced by tumor cells, intratumor stromal cells, such as fibroblasts, and intratumor leukocytes can attract different immune cell types into the tumor bed. References 1. Chemokines and chemokine receptors: positioning cells for host defense and immunity. Annu Rev Immunol. Charo I, Ransohoff R. The many roles of chemokines and chemokine receptors in inflammation.
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