Understanding the molecular mechanisms of the multifaceted IL‐10‐mediated anti‐inflammatory response: Lessons from neutrophils

Analysis of the molecular mechanisms governing the ability of IL‐10 to keep inflammation under control has highlighted the existence of a great degree of plasticity and specificity with regard to innate immune cells. In this respect, neutrophils represent a perfect example of innate immune cells conditioned by external signals (for instance, by LPS), as well as by intracellular regulatory pathways, that render them optimally responsive to IL‐10 only when required. The focus of this review are the recent experimental findings that have uncovered the sophisticated and complex molecular mechanisms responsible for the modulation of pro‐ and anti‐inflammatory cytokine production by IL‐10 in neutrophils and other innate immune cells. Understanding how IL‐10 exerts its anti‐inflammatory response, particularly in the case of neutrophils, will provide novel clues leading, hopefully, to the therapeutic control of neutrophil‐driven inflammatory reactions, such as septic infections, rheumatoid arthritis, osteoarthritis and chronic obstructive pulmonary disease.     

Caspase‐11 non‐canonical inflammasome: a critical sensor of intracellular lipopolysaccharide in macrophage‐mediated inflammatory responses

Inflammatory responses mediated by macrophages are part of the innate immune system, whose role is to protect against invading pathogens. Lipopolysaccharide (LPS) found in the outer membrane of Gram‐negative bacteria stimulates an inflammatory response by macrophages. During the inflammatory response, extracellular LPS is recognized by Toll‐like receptor 4, one of the pattern recognition receptors that activates inflammatory signalling pathways and leads to the production of inflammatory mediators. The innate immune response is also triggered by intracellular inflammasomes, and inflammasome activation induces pyroptosis and the secretion of pro‐inflammatory cytokines such as interleukin‐1β (IL‐1β) and IL‐18 by macrophages. Cysteine‐aspartic protease (caspase)‐11 and the human orthologues caspase‐4/caspase‐5 were recently identified as components of the ‘non‐canonical inflammasome’ that senses intracellular LPS derived from Gram‐negative bacteria during macrophage‐mediated inflammatory responses. Direct recognition of intracellular LPS facilitates the rapid oligomerization of caspase‐11/4/5, which results in pyroptosis and the secretion of IL‐1β and IL‐18. LPS is released into the cytoplasm from Gram‐negative bacterium‐containing vacuoles by small interferon‐inducible guanylate‐binding proteins encoded on chromosome 3 (GBP^chr3)‐mediated lysis of the vacuoles. In vivo studies have clearly shown that caspase‐11^−/− mice are more resistant to endotoxic septic shock by excessive LPS challenge. Given the evidence, activation of caspase‐11 non‐canonical inflammasomes by intracellular LPS is distinct from canonical inflammasome activation and provides a new paradigm in macrophage‐mediated inflammatory responses.     

Murine neutrophils treated with alphaB‐crystallin reduce IL‐12p40 production by dendritic cells

Neutrophils are essential in the fight against invading pathogens. They utilize antimicrobial effector mechanisms, such as phagocytosis, release of proteases and other antimicrobial products, robust oxidative bursts and neutrophil extracellular traps to combat infections. Neutrophils also modulate immune responses through the production of eicosanoids, cytokines and chemokines, as well as via direct communication with other immune cells. This system of high‐intensity offense against pathogens is exquisitely balanced through regulation to limit damage to host tissue. Unfortunately, the control of neutrophils is not failproof. In cases of sterile injury, autoimmunity and even during an infection, neutrophils can cause tissue destruction and become detrimental to the host. For that reason, there is a need to find means to regulate the aberrant activation of these cells. We found that alphaB‐crystallin (αBC), a heat‐shock protein known to have anti‐inflammatory abilities, affects certain properties of mouse neutrophils that subsequently influence the pro‐inflammatory state of antigen‐presenting cells (APCs). More specifically, αBC mediated small but significant increases in the levels of IL‐10 and matrix metalloproteinase 8, and altered hydrogen peroxide secretion by stimulated neutrophils. Further, the heat‐shock protein influenced the communication between neutrophils and dendritic cells by decreasing the production of pro‐inflammatory cytokines, specifically IL‐12p40, by the APCs. αBC could thus contribute to dampening neutrophil inflammatory responses by impacting the effect of neutrophils on other immune cells.     

The Gasdermin‐D pore acts as a conduit for IL‐1β secretion in mice

The pro‐inflammatory cytokine IL‐1β is well known for its role in host defense and the initiation of potent inflammatory responses. It is processed from its inactive pro‐form by the inflammatory caspase‐1 into its mature bioactive form, which is then released from the cell via an unconventional secretion mechanism. Recently, gasdermin‐D has been identified as a new target of caspase‐1. After proteolytical cleavage of gasdermin‐D, the N‐terminal fragment induces pyroptosis, a lytic cell death, by forming large permeability pores in the plasma membrane. Here we show using the murine system that gasdermin‐D is required for IL‐1β secretion by macrophages, dendritic cells and partially in neutrophils, and that secretion is a cell‐lysis‐independent event. Liposome transport assays in vitro further demonstrate that gasdermin‐D pores are large enough to allow the direct release of IL‐1β. Moreover, IL‐18 and other small soluble cytosolic proteins can also be released in a lysis‐independent but gasdermin‐D‐dependent mode, suggesting that the gasdermin‐D pores allow passive the release of cytosolic proteins in a size‐dependent manner.     

IL‐1R1–MyD88 axis elicits papain‐induced lung inflammation

Allergic asthma is characterized by a strong Th2 response with inflammatory cell recruitment and structural changes in the lung. Papain is a protease allergen disrupting the airway epithelium triggering a rapid inflammation with eosinophilia mediated by innate lymphoid cell activation (ILC2) and leading to a Th2 immune response. In this study, we focused on inflammatory responses to a single exposure to papain and showed that intranasal administration of papain results in the recruitment of inflammatory cells, including neutrophils and eosinophils with a rapid production of IL‐1α, IL‐1β, and IL‐33. The inflammatory response is abrogated in the absence of IL‐1R1 and MyD88. To decipher the cell type(s) involved in MyD88‐dependent IL‐1R1/MyD88 signaling, we used new cell‐specific MyD88‐deficient mice and found that the deletion of MyD88 signaling in single cell types such as T cells, epithelial cells, CD11c‐positive or myeloid cells leads to only a partial inhibition compared to complete absence of MyD88, suggesting that several cell types contribute to the response. Importantly, the inflammatory response is largely ST2 and IL‐36R independent. In conclusion, IL‐1R1 signaling via MyD88 is critical for the first step of inflammatory response to papain.     

Monocytes/macrophages and/or neutrophils are the target of IL‐10 in the LPS endotoxemia model

IL‐10 is a potent regulator of the innate and adaptive immune responses. Several cell types produce IL‐10 and its receptor chains and these may regulate different immune responses. Here we report that inactivation of the IL‐10 receptor (IL‐10R1) gene in mice leads to an increased susceptibility to chemically induced colitis as in the classical IL‐10‐deficient mutant. To identify the cells regulated by IL‐10 in immune responses, we generated several cell type specific IL‐10R1‐deficient mutants. We show that, in an IL‐10‐dependent LPS model of endotoxemia, dampening of the immune response requires expression of IL‐10R1 in monocytes/macrophages and/or neutrophils but not in T cells nor B cells. As the macrophage and/or neutrophil‐specific IL‐10‐deficient mutants also display the same phenotype, our results suggest that an autocrine loop in monocytes/macrophages is the most probable mechanism for the regulation of an LPS‐induced septic shock. In contrast, in an IL‐10‐regulated T‐cell response to Trichuris muris infection, IL‐10 acting on T cells or monocytes/macrophages/neutrophils is not critical for the control of the infection.     

NADPH oxidase derived reactive oxygen species are involved in human neutrophil IL‐1β secretion but not in inflammasome activation

Neutrophils are essential players in acute inflammatory responses. Upon stimulation, neutrophils activate NADPH oxidase, generating an array of reactive oxygen species (ROS). Interleukin‐1 beta (IL‐1β) is a major proinflammatory cytokine synthesized as a precursor that has to be proteolytically processed to become biologically active. The role of ROS in IL‐1β processing is still controversial and has not been previously studied in neutrophils. We report here that IL‐1β processing in human neutrophils is dependent on caspase‐1 and on the serine proteases elastase and/or proteinase 3. NADPH oxidase deficient neutrophils activated caspase‐1 and did not exhibit differences in NALP3 expression, indicating that ROS are neither required for inflammasome activation nor for its priming, as has been reported for macrophages. Strikingly, ROS exerted opposite effects on the processing and secretion of IL‐1β; whereas ROS negatively controlled caspase‐1 activity, as reported in mononuclear phagocytes, ROS were found to be necessary for the exportation of mature IL‐1β out of the cell, a role never previously described. The complex ROS‐mediated regulation of neutrophil IL‐1β secretion might constitute a physiological mechanism to control IL‐1β‐dependent inflammatory processes where neutrophils play a crucial role.     

Interferon lambda1/IL‐29 and inorganic polyphosphate are novel regulators of neutrophil‐driven thromboinflammation

Neutrophils and neutrophil‐released meshwork structures termed neutrophil extracellular traps (NETs) are major mediators of thromboinflammation and emerging targets for therapy, yet the mechanisms and pathways that control the role of neutrophils in thromboinflammation remain poorly understood. Here, we explored the role of IFN‐λ1/IL‐29, a major antiviral cytokine recently shown to suppress the neutrophil migratory capacity, in prothrombotic and proNETotic functions of neutrophils. In an ex vivo human experimental setting of acute ST‐segment elevation myocardial infarction (STEMI), we show that IFN‐λ1/IL‐29 hinders NET release and diminishes the amount of cytoplasmic TF in neutrophils. Since platelet–neutrophil interaction plays a major role in NET‐induced thromboinflammation, we further studied how IFN‐λ1/IL‐29 may interrupt this interaction. In this context, we identified inorganic polyphosphate (polyP) as a platelet‐derived NET inducer in STEMI. In arterial STEMI thrombi, polyP was present in platelets and in close proximity to NET remnants. PolyP release from activated platelets was dependent on thrombin present in infarcted artery plasma, resulting in NET formation by promoting mTOR inhibition and autophagy induction. The effect of polyP on mTOR inhibition was counteracted by IFN‐λ1/IL‐29 treatment, leading to inhibition of NET formation. Consistently, we show in an in vivo model of FeCl₃‐induced arterial thrombosis that IFN‐λ2/IL‐28A exerts strong antithrombotic potential. Taken together, these findings reveal a novel function of IFN‐λ1/IL‐29 in the suppression of thromboinflammation. Copyright © 2017 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.     

Card9‐dependent IL‐1β regulates IL‐22 production from group 3 innate lymphoid cells and promotes colitis‐associated cancer

Inflammatory bowel diseases (IBD) are key risk factors for the development of colorectal cancer, but the mechanisms that link intestinal inflammation with carcinogenesis are insufficiently understood. Card9 is a myeloid cell‐specific signaling protein that regulates inflammatory responses downstream of various pattern recognition receptors and which cooperates with the inflammasomes for IL‐1β production. Because polymorphisms in Card9 were recurrently associated with human IBD, we investigated the function of Card9 in a colitis‐associated cancer (CAC) model. Card9^?/? mice develop smaller, less proliferative and less dysplastic tumors compared to their littermates and in the regenerating mucosa we detected dramatically impaired IL‐1β generation and defective IL‐1β controlled IL‐22 production from group 3 innate lymphoid cells. Consistent with the key role of immune‐derived IL‐22 in activating STAT3 signaling during normal and pathological intestinal epithelial cell (IEC) proliferation, Card9^?/? mice also exhibit impaired tumor cell intrinsic STAT3 activation. Our results imply a Card9‐controlled, ILC3‐mediated mechanism regulating healthy and malignant IEC proliferation and demonstrates a role of Card9‐mediated innate immunity in inflammation‐associated carcinogenesis.     

IL‐15 dependent induction of IL‐18 secretion as a feedback mechanism controlling human MAIT‐cell effector functions

Mucosal‐associated invariant T (MAIT) cells are characterized by an invariant TCRVα7.2 chain recognizing microbial vitamin B metabolites presented by the MHC‐Ib molecule MR1. They are mainly detectable in the CD8⁺ and CD8^?CD4^? “double negative” T‐cell compartments of mammals and exhibit both Th1‐ and Th17‐associated features. As MAIT cells show a tissue‐homing phenotype and operate at mucosal surfaces with myriads of pathogenic encounters, we wondered how IL‐15, a multifaceted cytokine being part of the intestinal mucosal barrier, impacts on their functions. We demonstrate that in the absence of TCR cross‐linking, human MAIT cells secrete IFN‐γ, increase perforin expression and switch on granzyme B production in response to IL‐15. As this mechanism was dependent on the presence of CD14⁺ cells and sensitive to IL‐18 blockade, we identified IL‐15 induced IL‐18 production by monocytes as an inflammatory, STAT5‐dependent feedback mechanism predominantly activating the MAIT‐cell population. IL‐15 equally affects TCR‐mediated MAIT‐cell functions since it dramatically amplifies bacteria‐induced IFN‐γ secretion, granzyme production, and cytolytic activity at early time points, an effect being most pronounced under suboptimal TCR stimulation conditions. Our data reveal a new quality of IL‐15 as player in an inflammatory cytokine network impacting on multiple MAIT‐cell functions.     

IL‐33 broadens its repertoire to affect DC

IL‐33 is a novel multi‐functional IL‐1 family member that, in contrast to other family members, is associated with Th2 responses. IL‐33 signals via a heterodimer composed of its receptor, IL‐1 receptor‐like‐1 (IL‐1RL1), more commonly known as ST2L, and the IL‐1R accessory protein. ST2L is expressed by endothelial cells, mast cells, basophils, Th2 cells, and DC. IL‐33 has been associated with several immune‐mediated disorders, including asthma, arthritis, and inflammatory bowel disease. In contrast, there is evidence that IL‐33 can inhibit atherosclerosis development. A report in this issue of the European Journal of Immunology reveals a novel function of IL‐33: the ability to promote myeloid DC generation in murine BM cell cultures, by triggering GM‐CSF production by other BM cells, likely basophils. DC generated in the presence of IL‐33 are maturation resistant, with only minimal T‐cell stimulatory ability, associated with comparatively high levels of programmed death receptor ligand expression. This commentary discusses several questions raised by these findings, and provides a basis for further evaluation of IL‐33 and ST2L in regulation of APC generation and function in both innate and adaptive immunity.     

IL‐18 skews the invariant NKT‐cell population via autoreactive activation in atopic eczema

Atopic eczema (AE) is a chronic relapsing inflammatory skin disease where the commensal yeast Malassezia can act as a microbial trigger factor. Malassezia activates human DC to produce IL‐18, an innate cytokine that is elevated in serum of AE patients; however, the precise role of IL‐18 in human AE etiology is unknown. Herein, we investigated the effect of IL‐18 on the human invariant NKT (iNKT) cell compartment in AE. We found that IL‐18 was a potent activator of human iNKT‐cells and promoted a pro‐inflammatory CD1d‐dependent response, even in the absence of exogenous ligands. Chronic activation via IL‐18 on the other hand was inhibitory and skewed the iNKT‐cell pool by selectively suppressing CD4⁺ iNKT‐cells. This was mimicked in AE patients where the proportion of CD4⁺ iNKT‐cells was reduced in peripheral blood and coincided with elevated plasma levels of IL‐18. Furthermore, a reduced CD4⁺ iNKT‐cell pool was associated with elevated IgE levels in plasma, and the plasma levels of IL‐18 correlated with both total IgE and disease severity in the AE patients. Based on these findings, we propose that IL‐18‐mediated activation and subsequent dysregulation of the CD1d‐restricted iNKT‐cells plays a role in the pathogenesis of human AE.     

Reverse plasticity: TGF‐β and IL‐6 induce Th1‐to‐Th17‐cell transdifferentiation in the gut

Th17 cells are a heterogeneous population of pro‐inflammatory T cells that have been shown to mediate immune responses against intestinal bacteria. Th17 cells are highly plastic and can transdifferentiate to Th1/17 cells or unconventional Th1 cells, which are highly pathogenic in animal models of immune‐mediated diseases such as inflammatory bowel diseases. A recent European Journal of Immunology article by Liu et al. (Eur. J. Immunol. 2015. 45:1010–1018) showed, surprisingly, that Th1 cells have a similar plasticity, and could transdifferentiate to Th17 cells. Thus, IFN‐γ‐producing Th1 effector cells specific for an intestinal microbial antigen were shown to acquire IL‐17‐producing capacities in the gut in a mouse model of colitis, and in response to TGF‐β and IL‐6 in vitro. TGF‐β induced Runx1, and together with IL‐6 was shown to render the ROR‐γt and IL‐17 promoters in Th1 cells accessible for Runx1 binding. In this commentary, we discuss how this unexpected plasticity of Th1 cells challenges our view on the generation of Th1/17 cells with the capacity to co‐produce IL‐17 and IFN‐γ, and consider possible implications of this Th1‐to‐Th17‐cell conversion for therapies of inflammatory bowel diseases and protective immune responses against intracellular pathogens.     

Nasal IL‐17F is related to bronchial IL‐17F/neutrophilia and exacerbations in stable atopic severe asthma

Severe asthma (SA) is associated with neutrophil recruitment and T helper (T_H)17 chemokine overexpression in bronchial biopsies. We aimed to evaluate IL‐17A and IL‐17F expression in nasal/bronchial lamina propria of atopic mild‐to‐severe asthmatics and controls in relation to neutrophilia and asthma exacerbations. Cryostat sections of nasal/bronchial biopsies obtained from 14 SA and 14 mild asthma (MA) stable atopic patients with rhinitis, and seven healthy controls were analyzed by immunohistochemistry for neutrophils, IL‐17A and IL‐17F expression. Atopic SA showed an increase in asthma exacerbations number, IL‐17F and IL‐17A expression in nasal/bronchial lamina propria compared to MA and controls, and a higher expression of bronchial neutrophils in SA compared to MA and controls. In all asthmatics, significant relationships were found between bronchial IL‐17F and neutrophils/FEV₁, nasal IL‐17F and bronchial neutrophil/IL‐17 markers and between the latter and exacerbations, suggesting that nasal IL‐17F might be informative on bronchial IL17‐driven neutrophilia in atopic SA.     

IL‐18, but not IL‐15, contributes to the IL‐12‐dependent induction of NK‐cell effector functions by Leishmania infantum in vivo

Activation of NK cells is a hallmark of infections with intracellular pathogens. We previously showed that the protozoan parasite Leishmania infantum triggered a rapid NK‐cell response in mice that required TLR9‐positive myeloid DC and IL‐12, but no IFN‐α/β. Here, we investigated whether IL‐15 or IL‐18 mediate the activity of IL‐12 or function as independent activators of NK cells. In contrast to earlier studies that described IL‐15 as crucial for NK‐cell priming in response to TLR ligands, the expression of IFN‐γ, FasL, perforin and granzyme B by NK cells in L. infantum‐infected mice was completely preserved in the absence of IL‐15, whereas the proliferative capacity of NK cells was lower than in WT mice. IFN‐γ secretion, cytotoxicity and FasL expression of NK cells from infected IL‐18^?/? mice were significantly reduced compared with controls, but, unlike IL‐12, IL‐18 was not essential for NK‐cell effector functions. Part of the NK‐cell‐stimulatory effect of IL‐12 was dependent on IL‐18. We conclude that IL‐15 is not functioning as a universal NK‐cell priming signal and that IL‐18 contributes to the NK‐cell response in visceral leishmaniasis. The cytokine requirements for NK‐cell activation appear to differ contingent upon the infectious pathogen.     

Staphylococcus epidermidis from prosthetic joint infections induces lower IL‐1β release from human neutrophils than isolates from normal flora

The aim of this study was to test the hypothesis that Staphylococcus epidermidis isolated from prosthetic joint infections (PJIs) differs from S. epidermidis isolated from normal flora in terms of its capacity to induce activation of caspase‐1 and release of IL‐1β in human neutrophils. The amount of active caspase‐1 was determined over 6 h by detecting Ac‐YVAD‐AMC fluorescence in human neutrophils incubated with S. epidermidis isolates from PJIs (ST2) or normal flora. The amount of IL‐1β was detected by ELISA in neutrophil supernatants after 6 h of incubation. Mean IL‐1β release was lower after incubation with S. epidermidis from PJIs compared to isolates from normal flora, but no statistically significant difference was found in active caspase‐1. Substantial inter‐individual differences in both active caspase‐1 and IL‐1β were noted. These results suggest that evasion of innate immune response, measured as reduced capacity to induce release of IL‐1β from human neutrophils, might be involved in the predominance of ST2 in S. epidermidis PJIs, but that other microbe‐related factors are probably also important.     

IL‐22 modulates IL‐17A production and controls inflammation and tissue damage in experimental dengue infection

Dengue virus (DENV), a mosquito‐borne flavivirus, is a public health problem in many tropical countries. IL‐22 and IL‐17A are key cytokines in several infectious and inflammatory diseases. We have assessed the contribution of IL‐22 and IL‐17A in the pathogenesis of experimental dengue infection using a mouse‐adapted DENV serotype 2 strain (P23085) that causes a disease that resembles severe dengue in humans. We show that IL‐22 and IL‐17A are produced upon DENV‐2 infection in immune‐competent mice. Infected IL‐22^?/? mice had increased lethality, neutrophil accumulation and pro‐inflammatory cytokines in tissues, notably IL‐17A. Viral load was increased in spleen and liver of infected IL‐22^?/? mice. There was also more severe liver injury, as seen by increased transaminases levels and tissue histopathology. γδ T cells and NK cells are sources of IL‐17A and IL‐22, respectively, in liver and spleen. We also show that DENV‐infected HepG2 cells treated with rhIL‐22 had reduced cell death and decreased IL‐6 production. IL‐17RA^?/? mice were protected upon infection and IL‐17A‐neutralizing‐Ab‐treatment partially reversed the phenotype observed in IL‐22^?/?‐infected mice. We suggest that disrupting the balance between IL‐22 and IL‐17A levels may represent an important strategy to reduce inflammation and tissue injury associated with severe dengue infection.     

IL‐10 differentially controls the infiltration of inflammatory macrophages and antigen‐presenting cells during inflammation

The inflammatory activation and recruitment of defined myeloid populations is essential for controlling the bridge between innate and adaptive immunity and shaping the immune response to microbial challenge. However, these cells exhibit significant functional heterogeneity and the inflammatory signals that differentially influence their effector characteristics are poorly characterized. In this study, we defined the phenotype of discrete subsets of effective antigen‐presenting cells (APCs) in the peritoneal cavity during peritonitis. When the functional properties of these cells were compared to inflammatory monocyte‐derived macrophages we noted differential responses to the immune‐modulatory cytokine IL‐10. In contrast to the suppressive actions of IL‐10 on inflammatory macrophages, the recruitment of APCs was relatively refractory and we found no evidence for selective inhibition of APC differentiation. This differential response of myeloid cell subsets to IL‐10 may thus have limited impact on development of potentially tissue‐damaging adaptive immune responses, while restricting the magnitude of the inflammatory response. These findings may have clinical relevance in the context of peritoneal dialysis patients, where recurrent infections are associated with immune‐mediated membrane dysfunction, treatment failure, and increased morbidity.     

IL‐Y,a synthetic member of the IL‐12 cytokine family,suppresses the development of type 1 diabetes in NOD mice

The IL‐12 family of heterodimeric cytokines, consisting of IL‐12, IL‐23, IL‐27, and IL‐35, has important roles in regulating the immune response. IL‐12 family members are comprised of a heterodimer consisting of α and β chains: IL‐12 (p40 and p35), IL‐23 (p40 and p19), IL‐27 (Ebi3 and p28), and IL‐35 (Ebi3 and p35). Given the combinatorial nature of the IL‐12 family, we generated adenoviral vectors expressing two putative IL‐12 family members not yet found naturally, termed IL‐X (Ebi3 and p19) and IL‐Y (p40 and p28), as single‐chain molecules. Single chain IL‐Y (scIL‐Y), but not scIL‐X, was able to stimulate significantly a unique cytokine/chemokine expression profile as well as activate STAT3 in mice, in part, through a pathway involving IL‐27Rα in splenocytes. Adenoviral‐mediated, intratumoral delivery of scIL‐Y increased tumor growth in contrast to the anti‐tumor effects of scIL‐12 and scIL‐23. Similarly, treatment of prediabetic NOD mice by intravenous injection of Ad.scIL‐Y prevented the onset of hyperglycemia. Analysis of cells from Ad.scIL‐Y‐treated NOD mice demonstrated that scIL‐Y reduced expression of inflammatory mediators such as IFN‐γ. Our data demonstrate that a novel, synthetic member of the IL‐12 family, termed IL‐Y, confers unique immunosuppressive effects in two different disease models and thus could have therapeutic applications.