IL-17 Receptor Signaling through IL-17A or IL-17F Is Sufficient to Maintain Innate Response and Control of Helicobacter pylori Immunopathogenesis

Abstract

IL-17R signaling is required for control of extracellular pathogens and is also implicated in development of chronic inflammatory processes. The response to the human pathogen Helicobacter pylori results in Th1 and Th17 cell activation and a chronic inflammatory process that can lead to adverse outcomes, such as gastric cancer. Previously, we identified IL-17RA as a requirement for the recruitment of neutrophils and control of H. pylori colonization in the gastric mucosa. Unexpectedly, H. pylori-infected Il17ra À/À mice had significantly more chronic inflammation than H. pylori-infected wild-type mice. In this study, human epithelial cell lines and murine models were used to investigate differential roles for IL-17A, IL-17F, and IL-17A/F during H. pylori infection. Moreover, the hypothesis that IL-17RA signaling, specifically in lymphocytes, provides an autocrine feedback loop that downregulates Th17 cytokine production was investigated. The data indicate that epithelial cells exhibit a stronger response to IL-17A and IL-17A/F than IL-17F, and that IL-17A and IL-17A/F can synergize with TNF and IL-22 to induce antimicrobial genes of gastric epithelial cells. In vivo deficiencies of IL-17A or IL-17F alone did not significantly change the immunopathological response to H. pylori, but if both cytokines were absent, a hyperinflammatory lymphocytic response developed. Using a cre/flox targeting approach for IL-17RA combined with infection, our findings demonstrate that increased chronic inflammation in Il17ra À/À mice was not attributed to a T cell-intrinsic defect. These data imply that IL-17A and IL-17F may have overlapping roles in maintenance of the gastric mucosal response to infection. ImmunoHorizons, 2022, 6: 116-129.

An elevated level of interleukin-17A in a Senegalese malaria cohort is associated with rs8193038 IL-17A genetic variant

“…Recently, the IL-17 proinflammatory cytokine has gained attention among malaria researchers because of its protective role in immunity against extracellular pathogens [ 6 – 8 ] and for the clearance of intracellular pathogens [ 9 – 11 ]. In addition to its essential role in protective immunity, IL-17 is critical in the pathogenesis of various autoimmune inflammatory diseases.…”

Role of IL-6/STAT3 Axis in Resistance to Cisplatin in Gastric Cancers

“…Consequently, in oncology, IL-6/STAT3 is the target of several therapies. IL-6 and STAT3 inhibition may represent a likely target that could revert acquired resistance [ 39 ]. In this context, increased IL-6 secretion, together with the upregulation of GP130, the IL-6 receptor, is likely responsible for increased STAT3 expression and poor sensitivity to treatment with chemotherapeutic agents.…”

An elevated level of Interleukin-17A in a Senegalese malaria cohort is associated with rs8193038 IL-17A genetic variant

“…Recently, the IL-17 proin ammatory cytokine has gained attention among malaria researchers because of its protective role in immunity against extracellular pathogens [5][6][7] and for the clearance of intracellular pathogens [8][9][10]. In addition to its essential role in protective immunity, IL-17 is critical in the pathogenesis of various autoimmune in ammatory diseases.…”