Arginase I Suppresses IL-12/IL-23p40–Driven Intestinal Inflammation during Acute Schistosomiasis

Abstract

Alternatively activated macrophages prevent lethal intestinal pathology caused by worm ova in mice infected with the human parasite Schistosoma mansoni through mechanisms that are currently unclear. This study demonstrates that arginase I (Arg I), a major product of IL-4– and IL-13–induced alternatively activated macrophages, prevents cachexia, neutrophilia, and endotoxemia during acute schistosomiasis. Specifically, Arg I-positive macrophages promote TGF-β production and Foxp3 expression, suppress Ag-specific T cell proliferation, and limit Th17 differentiation. S. mansoni-infected Arg I-deficient bone marrow chimeras develop a marked accumulation of worm ova within the ileum but impaired fecal egg excretion compared with infected wild-type bone marrow chimeras. Worm ova accumulation in the intestines of Arg I-deficient bone marrow chimeras was associated with intestinal hemorrhage and production of molecules associated with classical macrophage activation (increased production of IL-6, NO, and IL-12/IL-23p40), but whereas inhibition of NO synthase-2 has marginal effects, IL-12/IL-23p40 neutralization abrogates both cachexia and intestinal inflammation and reduces the number of ova within the gut. Thus, macrophage-derived Arg I protects hosts against excessive tissue injury caused by worm eggs during acute schistosomiasis by suppressing IL-12/IL-23p40 production and maintaining the Treg/Th17 balance within the intestinal mucosa.

Macrophage arginase-1 controls bacterial growth and pathology in hypoxic tuberculosis granulomas

“…Moreover, Arg1-expressing cells accumulate in and around S. mansoni granulomas (30,55,56) and in skin lesions from patients who have cutaneous leishmaniasis (57); these lesions often are necrotic and hypoxic (58,59). In murine S. mansoni infection, Arg1-expressing macrophages restrain Th2 cytokinedriven inflammation and fibrosis (30,60). Notably, during Leishmania infection in mice, Arg1 contributes to the failure to heal persistent lesions, which is a consequence of impaired T-cell responses to L. major resulting from local depletion of L-arginine by arginase (32).…”

Immunity to gastrointestinal nematode infections

“…75,192,203,204 Furthermore, macrophages in the intestinal mucosa are also likely to play an important role in tissue repair, as has been shown in various settings of inflammation. [205][206][207][208][209][210] Whereas most research on host-parasite interactions has focused on the underlying factors that govern resistance and susceptibility, the long-term consequences of both acute and chronic worm infections are largely unexplored. Given the inverse correlation between parasite exposure and the occurrence of immune-associated disorders, it is quite surprising that so little attention has been devoted to this subject, particularly in the case of Trichuris infections that have been in clinical trial for the treatment of various inflammatory disorders.…”

IL-33 drives biphasic IL-13 production for noncanonical Type 2 immunity against hookworms

“…Real-time PCR was carried out on a Biorad iCycler (Hercules) or CFX Connect (Bio-Rad) with the Syber Green detection reagent. Cycle threshold (CT) values for genes evaluated were determined and expressed using the 1/ΔΔ ct method, as described previously (52).…”