Caracterização de mecanismos induzidos pela infecção por Strongyloides venezuelensis que atuam na modulação da retocolite ulcerativa provocada por Sulfato de Sódio Dextrano em camundongos

Abstract

Helminth infection induces a modulated type-2 immune response, which may alter other chronic inflammatory diseases, such as ulcerative colitis. Previous data from our study group have demonstrated that concomitant acute Strongyloides venezuelensis infection with DSS treatment was able to reduce the clinical severity of colitis DSS-induced, however the mechanisms involved have not been clarified. Herein, we evaluated possible immunological mechanisms induced by S. venezuelensis infection and/or its antigens that participate in the modulation of acute and chronic ulcerative colitis caused by DSS in mice. For the experiment, wild‐type BALB/c mice (WT) was infected with S. venezuelensis or inoculated with their antigens and they were treated orally with DSS solution to induce acute or chronic colitis. As controls, we used uninfected and untreated mice, only infected, and only treated with DSS. In some experiments, the experimental procedure was performed on BALB/c mice deficient in IL-33 receptor production (ST2 -/ -), deficient in IL-4 production (IL-4 -/-), deficient in eosinophil maturation (∆dblGATA) to investigate the role of these elements in the mechanism of colitis induction and modulation. Subsequently, the ability of a PBS-soluble extract of adult S. venezuelensis to suppress macrophage (human THP-1 cell line) response to in vitro challenge with lipopolysaccharide (LPS) was tested. The results showed that active S. venezuelensis infection concomitantly with the induction of UC reduces clinical signs, colon treatment, distal colon inflammation and Th-1 and Th-17 cytokines/chemokines, while increased Th-2 and Treg cytokines. However, previous S. venezuelensis infection and/or inoculation of soluble parasite antigens in low concentrations does not reduce clinical severity and damage to the colon mucosa. Animals that became infected after the establishment of chronic DSS-induced colitis had reduced clinical signs, colon shortening and colonic mucosal inflammation, while they had increased regulatory cytokines and repair of mucosa. Mice deficient in Th-2 response induction, such as production of ST2 receptor (ST2-/-), cytokine IL-4 (IL-4-/-) and eosinophil differentiation (ΔdblGATA) had lower clinical and microscopic scores compared to wild mice. However, S. venezuelensis-infected ST2-/- mice showed a reduction in clinical score, colon shortening, and colonic mucosal damage compared to ST2-/- mice treated with DSS only, but without an increase in IL- 10 and IL-13. In IL-4 -/- mice, the nematode infection did not reduce the clinical score of colitis but reduced the tissue damage of the colon. In ΔdblGATA mice, infection was not able to decrease weight loss, clinical score, or inflammation of the distal colon. Our data also showed that treated-DSS/infected WT mice showed faster recovery from DSS-induced colitis and increased arginase activity by cells isolated from the peritoneal lavage than treated animals only. In ST2 -/- infected and treated mice had clinical worsening after cessation of exposure to DSS, while infected and treated IL-4 -/- and ∆dblGATA mice presented colitis recovery kinetics similar to those treated with DSS only. Finally, S. venezuelensis adult worm antigens reduced the production of TNF-α and IL-1 by LPS-stimulated THP-1 cells in vitro. In summary, active infection by S. venezuelensis induce Th-2 and regulatory immune response with activation of M2, which act to reduce the severity of acute colitis DSS-induced by eosinophil-dependent and IL-33/ST2 -independent repair mechanisms. Active nematode infection also modulates chronic colitis by the participation of repair cytokines such as TGF-β.