Arginase I suppresses IL-12/IL-23p40-driven intestinal inflammation during acute schistosomiasis.
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-beta 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.
Herbert
De'Broski R
DR
Research Service, Cincinnati Veterans Administration Medical Center, Cincinnati, OH 45220, USA. debroski.herbert@cchmc.org
Orekov
Tatyana
T
Roloson
Amanda
A
Ilies
Monica
M
Perkins
Charles
C
O'Brien
William
W
Cederbaum
Stephen
S
Christianson
David W
DW
Zimmermann
Nives
N
Rothenberg
Marc E
ME
Finkelman
Fred D
FD
D000818:Animals; D001119:Arginase / Q000276:immunology* / Q000378:metabolism; D002454:Cell Differentiation; D002469:Cell Separation; D018920:Coculture Techniques; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D005434:Flow Cytometry; D007150:Immunohistochemistry; D007249:Inflammation / Q000276:immunology* / Q000378:metabolism; D018664:Interleukin-12 / Q000276:immunology* / Q000378:metabolism; D053759:Interleukin-23 / Q000276:immunology* / Q000378:metabolism; D007413:Intestinal Mucosa / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D008213:Lymphocyte Activation / Q000276:immunology; D008262:Macrophage Activation / Q000276:immunology; D008264:Macrophages / Q000276:immunology / Q000378:metabolism; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D019948:Receptors, Interleukin-4 / Q000276:immunology / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012555:Schistosomiasis mansoni / Q000276:immunology* / Q000378:metabolism; D013601:T-Lymphocytes / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D018183:Transplantation Chimera
D053759:Interleukin-23; D019948:Receptors, Interleukin-4; D018664:Interleukin-12; C544448:Arg1 protein, mouse; D001119:Arginase