transforming-growth-factor-beta and Hookworm-Infections

The mucosal cytokine response of healthy humans to parasitic helminths has never been reported. We investigated the systemic and mucosal cytokine responses to hookworm infection in experimentally infected, previously hookworm naive individuals from non-endemic areas. We collected both peripheral blood and duodenal biopsies to assess the systemic immune response, as well as the response at the site of adult worm establishment. Our results show that experimental hookworm infection leads to a strong systemic and mucosal Th2 (IL-4, IL-5, IL-9 and IL-13) and regulatory (IL-10 and TGF-β) response, with some evidence of a Th1 (IFN-γ and IL-2) response. Despite upregulation after patency of both IL-15 and ALDH1A2, a known Th17-inducing combination in inflammatory diseases, we saw no evidence of a Th17 (IL-17) response. Moreover, we observed strong suppression of mucosal IL-23 and upregulation of IL-22 during established hookworm infection, suggesting a potential mechanism by which Th17 responses are suppressed, and highlighting the potential that hookworms and their secreted proteins offer as therapeutics for human inflammatory diseases.

Topics: Aldehyde Dehydrogenase 1 Family; Ancylostomatoidea; Animals; Antigens, Helminth; Australia; Autoimmunity; Diet, Gluten-Free; Hookworm Infections; Human Experimentation; Humans; Immunity, Mucosal; Interleukins; Larva; Mucous Membrane; Parasite Egg Count; Retinal Dehydrogenase; Single-Blind Method; Th1 Cells; Th2 Cells; Transforming Growth Factor beta

Transforming growth factor β (TGF-β) regulates inflammation, immunosuppression, and wound-healing cascades, but it remains unclear whether any of these functions involve regulation of myeloid cell function. The present study demonstrates that selective deletion of TGF-βRII expression in myeloid phagocytes i) impairs macrophage-mediated suppressor activity, ii) increases baseline mRNA expression of proinflammatory chemokines/cytokines in the lung, and iii) enhances type 2 immunity against the hookworm parasite Nippostrongylus brasiliensis. Strikingly, TGF-β-responsive myeloid cells promote repair of hookworm-damaged lung tissue, because LysM(Cre)TGF-βRII(flox/flox) mice develop emphysema more rapidly than wild-type littermate controls. Emphysematous pathology in LysM(Cre)TGF-βRII(flox/flox) mice is characterized by excessive matrix metalloprotease (MMP) activity, reduced lung elasticity, increased total lung capacity, and dysregulated respiration. Thus, TGF-β effects on myeloid cells suppress helminth immunity as a consequence of restoring lung function after infection.

Topics: Animals; Bone Marrow Cells; Emphysema; Hookworm Infections; Immunity; Lung; Lymphocyte Activation; Macrophages, Alveolar; Matrix Metalloproteinases; Mice; Mice, Inbred C57BL; Mice, Knockout; Myeloid Cells; Nippostrongylus; Pneumonia; Protein Serine-Threonine Kinases; Pulmonary Fibrosis; Receptor, Transforming Growth Factor-beta Type II; Receptors, Transforming Growth Factor beta; T-Lymphocytes; Transforming Growth Factor beta; Wound Healing