Journal
JOURNAL OF LEUKOCYTE BIOLOGY
Volume 104, Issue 4, Pages 855-869Publisher
OXFORD UNIV PRESS
DOI: 10.1002/JLB.4A0917-369RR
Keywords
bone marrow chimera; inflammation; lung; macrophage; parasitic-helminth
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Funding
- NIH [1R01AI091759-01A1, R21AI137830, K22AI119155, R21AI135500]
- UCR School of Medicine initial complement
- UCR Academic Senate
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Resistin-like molecule alpha (RELM alpha) is a highly secreted protein in type 2 (Th2) cytokine-induced inflammation including helminth infection and allergy. In infection with Nippostrongylus brasiliensis (Nb), RELM alpha dampens Th2 inflammatory responses. RELM alpha is expressed by immune cells, and by epithelial cells (EC); however, the functional impact of immune versus EC-derived RELM alpha is unknown. We generated bone marrow (BM) chimeras that were RELM alpha deficient (RELM alpha(-/-)) in BM or non BM cells and infected them with Nb. Non BM RELM alpha(-/-) chimeras had comparable inflammatory responses and parasite burdens to RELM alpha(+/+) mice. In contrast, both RELM alpha(-/-) and BM RELM alpha(-/-) mice exhibited increased Nb-induced lung and intestinal inflammation, correlated with elevated Th2 cytokines and Nb killing. CD11c(+) lung macrophages were the dominant BM-derived source of RELM alpha and can mediate Nb killing. Therefore, we employed a macrophage-worm co-culture system to investigate whether RELM alpha regulates macrophage-mediated Nb killing. Compared to RELM alpha(+/+) macrophages, RELM alpha(-/-) macrophages exhibited increased binding to Nb and functionally impaired Nb development. Supplementation with recombinant RELM alpha partially reversed this phenotype. Gene expression analysis revealed that RELM alpha decreased cell adhesion and Fc receptor signaling pathways, which are associated with macrophage-mediated helminth killing. Collectively, these studies demonstrate that BM-derived RELM alpha is necessary and sufficient to dampen Nb immune responses, and identify that one mechanism of action of RELM alpha is through inhibiting macrophage recruitment and interaction with Nb. Our findings suggest that RELM alpha acts as an immune brake that provides mutually beneficial effects for the host and parasite by limiting tissue damage and delaying parasite expulsion.
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