IL-22 mediates host defense against an intestinal intracellular parasite in the absence of IFN-γ at the cost of Th17-driven immunopathology.
ABSTRACT The roles of Th1 and Th17 responses as mediators of host protection and pathology in the intestine are the subjects of intense research. In this study, we investigated a model of intestinal inflammation driven by the intracellular apicomplexan parasite Eimeria falciformis. Although IFN-γ was the predominant cytokine during E. falciformis infection in wild-type mice, it was found to be dispensable for host defense and the development of intestinal inflammation. E. falciformis-infected IFN-γR(-/-) and IFN-γ(-/-) mice developed dramatically exacerbated body weight loss and intestinal pathology, but they surprisingly harbored fewer parasites. This was associated with a striking increase in parasite-specific IL-17A and IL-22 production in the mesenteric lymph nodes and intestine. CD4(+) T cells were found to be the source of IL-17A and IL-22, which drove the recruitment of neutrophils and increased tissue expression of anti-microbial peptides (RegIIIβ, RegIIIγ) and matrix metalloproteinase 9. Concurrent neutralization of IL-17A and IL-22 in E. falciformis-infected IFN-γR(-/-) mice resulted in a reduction in infection-induced body weight loss and inflammation and significantly increased parasite shedding. In contrast, neutralization of IL-22 alone was sufficient to increase parasite burden, but it had no effect on body weight loss. Treatment of an E. falciformis-infected intestinal epithelial cell line with IFN-γ, IL-17A, or IL-22 significantly reduced parasite development in vitro. Taken together, to our knowledge these data demonstrate for the first time an antiparasite effect of IL-22 during an intestinal infection, and they suggest that IL-17A and IL-22 have redundant roles in driving intestinal pathology in the absence of IFN-γ signaling.
- SourceAvailable from: Idit Shachar[show abstract] [hide abstract]
ABSTRACT: Cytokines and chemokines are secreted, small cell-signaling protein molecules, whose receptors are expressed on immune cells. These factors play a critical role in immune cell differentiation, migration, and polarization into functional subtypes and in directing their biological functions. Much attention has been devoted to exploring the role of key inflammatory cytokines and promigratory chemokines in autoimmune, autoinflammatory, and allergic diseases, leading to development of therapeutic strategies that are based on their targeted neutralization. Recent studies, including those coming from our groups, show that several major proinflammatory cytokines and chemokines, including IFN-γ, IL-2, CCL2, and CXCL12, may also function as anti-inflammatory mediators and therefore, may have potential as anti-inflammatory drugs. Likewise, major anti-inflammatory mediators, such as TGF-β, may under certain conditions, in combination with other cytokines, exhibit proinflammatory function and direct the polarization of the highly inflammatory CD4(+) Th17 cells. We show here that the biological function of pro- and anti-inflammatory cytokines is dependent on three key parameters: the local concentration of a given cytokine, the stage of disease in which it is administered, and its combination with other cytokines. The therapeutic implications of these findings are discussed, including two very recent studies summarizing clinical trials, in which low-dose administration of IL-2 was used to successfully suppress HCV and GVHD.Journal of leukocyte biology 09/2012; · 4.99 Impact Factor
- [show abstract] [hide abstract]
ABSTRACT: Interleukin (IL)-22 has redundant, protective or pathogenic functions during auto-immune, inflammatory and infectious diseases. Here, we addressed the potential role of IL-22 in host defence and pathogenesis during lethal and sublethal respiratory H3N2 influenza A virus (IAV) infection. We show that IL-22, as well as factors associated with its production, are expressed in the lung tissue during the early phases of IAV infection. Our data indicate that RORγt-positive αβ and γδ T cells, as well as innate lymphoid cells, expressed enhanced Il22 transcripts as early as two days post-infection. During lethal or sublethal IAV infections, endogenous IL-22 played no role in the control of IAV replication and in the development of the IAV-specific CD8(+) T cell response. During lethal infection, where wild-type (WT) mice succumbed to severe pneumonia, the lack of IL-22 did not accelerate or delay IAV-associated pathogenesis and animal death. In stark contrast, during sublethal IAV infection, IL-22 deficient animals had an enhanced lung injury and showed a lower airway epithelial integrity relative to WT littermates. Of importance, the protective effect of endogenous IL-22 in pulmonary damages was associated with a more controlled secondary bacterial infection. Indeed, after challenge with Streptococcus pneumoniae, IAV-experienced Il22(-/-) animals were more susceptible than WT controls in terms of survival rate and bacterial burden in the lungs. Together, IL-22 plays no major role during lethal influenza but is beneficial during sublethal H3N2 IAV infection where it limits lung inflammation and subsequent bacterial superinfections.Journal of Virology 04/2013; · 5.08 Impact Factor
- [show abstract] [hide abstract]
ABSTRACT: Anti-inflammatory treatment of autoimmune diseases is associated with an increased risk of reactivation tuberculosis (TB). Besides interleukin (IL-17)A, IL-22 represents a classical T helper (TH)17 cytokine and shares similar pathological effects in inflammatory diseases such as psoriasis or arthritis. Whereas IL-17A supports protective immune responses during mycobacterial infections, the role of IL-22 after infection with () is yet poorly characterized. Therefore, we here characterize the cell types producing IL-22 and the protective function of this cytokine during experimental TB in mice. Like IL-17A, IL-22 is expressed early after infection with in an IL-23-dependent manner. Surprisingly, the majority of IL-22-producing cells are not positive for IL-17A but have rather functional characteristics of interferon-gamma-producing TH1 cells. Although we found minor differences in the number of naive and central memory T cells as well as in the frequency of TH1 and polyfunctional T cells in mice deficient for IL-22, the absence of IL-22 does not affect the outcome of infection. Our study revealed that although produced by TH1 cells, IL-22 is dispensable for protective immune responses during TB. Therefore, targeting of IL-22 in inflammatory disease may represent a therapeutic approach that does not incur the danger of reactivation TB.PLoS ONE 01/2013; 8(2):e57379. · 3.73 Impact Factor