Hematopoietic cell-derived RELMalpha regulates hookworm immunity through effects on macrophages.

Adenosine Triphosphate/metabolism; Alveolar Epithelial Cells/metabolism; Animals; Cell Adhesion; Cells, Cultured; Coculture Techniques; Dendritic Cells/metabolism; Female; Gene Expression Regulation; Intercellular Signaling Peptides and Proteins/deficiency/genetics/physiology; Macrophages, Alveolar/immunology; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Nippostrongylus/isolation & purification/ultrastructure; Radiation Chimera; Recombinant Proteins/metabolism; Strongylida Infections/immunology/parasitology; Th2 Cells/immunology; bone marrow chimera; inflammation; lung; macrophage; parasitic-helminth

Abstract :

[en] Resistin-like molecule alpha (RELMalpha) is a highly secreted protein in type 2 (Th2) cytokine-induced inflammation including helminth infection and allergy. In infection with Nippostrongylus brasiliensis (Nb), RELMalpha dampens Th2 inflammatory responses. RELMalpha is expressed by immune cells, and by epithelial cells (EC); however, the functional impact of immune versus EC-derived RELMalpha is unknown. We generated bone marrow (BM) chimeras that were RELMalpha deficient (RELMalpha(-/) (-) ) in BM or non BM cells and infected them with Nb. Non BM RELMalpha(-/-) chimeras had comparable inflammatory responses and parasite burdens to RELMalpha(+/+) mice. In contrast, both RELMalpha(-/-) and BM RELMalpha(-/-) 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 RELMalpha and can mediate Nb killing. Therefore, we employed a macrophage-worm co-culture system to investigate whether RELMalpha regulates macrophage-mediated Nb killing. Compared to RELMalpha(+) (/+) macrophages, RELMalpha(-/-) macrophages exhibited increased binding to Nb and functionally impaired Nb development. Supplementation with recombinant RELMalpha partially reversed this phenotype. Gene expression analysis revealed that RELMalpha decreased cell adhesion and Fc receptor signaling pathways, which are associated with macrophage-mediated helminth killing. Collectively, these studies demonstrate that BM-derived RELMalpha is necessary and sufficient to dampen Nb immune responses, and identify that one mechanism of action of RELMalpha is through inhibiting macrophage recruitment and interaction with Nb. Our findings suggest that RELMalpha acts as an immune brake that provides mutually beneficial effects for the host and parasite by limiting tissue damage and delaying parasite expulsion.

Disciplines :

Biochemistry, biophysics & molecular biology

Author, co-author :

Batugedara, Hashini Maneesha ; Université de Liège - ULiège > I3-Cellular and Molecular Immunology

Li, Jiang

Chen, Gang

Lu, Dihong

Patel, Jay J.

Jang, Jessica C.

Radecki, Kelly C.

Burr, Abigail C.

Lo, David D.

Dillman, Adler R.

Nair, Meera G.

Language :

English

Title :

Hematopoietic cell-derived RELMalpha regulates hookworm immunity through effects on macrophages.

Publication date :

2018

Journal title :

Journal of Leukocyte Biology

ISSN :

0741-5400

Publisher :

Federation of American Societies for Experimental Biology, United States - New York

Volume :

104

Issue :

Pages :

855-869

Peer reviewed :

Peer Reviewed verified by ORBi

Commentary :

Available on ORBi :

since 27 May 2019

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