title: Macrophage-derived human resistin is induced in multiple helminth infections and promotes inflammatory monocytes and increased parasite burden.
abstract: Parasitic helminth infections can be associated with lifelong morbidity such as immune-mediated organ failure. A better understanding of the host immune response to helminths could provide new avenues to promote parasite clearance and/or alleviate infection-associated morbidity. Murine resistin-like molecules (RELM) exhibit pleiotropic functions following helminth infection including modulating the host immune response; however, the relevance of human RELM proteins in helminth infection is unknown. To examine the function of human resistin (hResistin), we utilized transgenic mice expressing the human resistin gene (hRetnTg+). Following infection with the helminth Nippostrongylus brasiliensis (Nb), hResistin expression was significantly upregulated in infected tissue. Compared to control hRetnTg- mice, hRetnTg+ mice suffered from exacerbated Nb-induced inflammation characterized by weight loss and increased infiltration of inflammatory monocytes in the lung, along with elevated Nb egg burdens and delayed parasite expulsion. Genome-wide transcriptional profiling of the infected tissue revealed that hResistin promoted expression of proinflammatory cytokines and genes downstream of toll-like receptor signaling. Moreover, hResistin preferentially bound lung monocytes, and exogenous treatment of mice with recombinant hResistin promoted monocyte recruitment and proinflammatory cytokine expression. In human studies, increased serum resistin was associated with higher parasite load in individuals infected with soil-transmitted helminths or filarial nematode Wuchereria bancrofti, and was positively correlated with proinflammatory cytokines. Together, these studies identify human resistin as a detrimental factor induced by multiple helminth infections, where it promotes proinflammatory cytokines and impedes parasite clearance. Targeting the resistin/proinflammatory cytokine immune axis may provide new diagnostic or treatment strategies for helminth infection and associated immune-mediated pathology.
authors.affiliation: Division of Biomedical Sciences, School of Medicine, University of California Riverside, Riverside, California, United States of America.
authors.forename: Jessica C
authors.initials: JC
authors.lastname: Jang
authors.affiliation: Division of Biomedical Sciences, School of Medicine, University of California Riverside, Riverside, California, United States of America.
authors.forename: Gang
authors.initials: G
authors.lastname: Chen
authors.affiliation: Division of Biomedical Sciences, School of Medicine, University of California Riverside, Riverside, California, United States of America.
authors.forename: Spencer H
authors.initials: SH
authors.lastname: Wang
authors.affiliation: Division of Biomedical Sciences, School of Medicine, University of California Riverside, Riverside, California, United States of America.
authors.forename: Mark A
authors.initials: MA
authors.lastname: Barnes
authors.affiliation: Division of Biomedical Sciences, School of Medicine, University of California Riverside, Riverside, California, United States of America.
authors.forename: Josiah I
authors.initials: JI
authors.lastname: Chung
authors.affiliation: Malaghan Institute of Medical Research, Wellington, New Zealand.
authors.forename: Mali
authors.initials: M
authors.lastname: Camberis
authors.affiliation: Malaghan Institute of Medical Research, Wellington, New Zealand.
authors.forename: Graham
authors.initials: G
authors.lastname: Le Gros
authors.affiliation: Laboratorio de Investigaciones FEPIS, Quinindé, Ecuador; Centro de Investigación en Enfermedades Infecciosas, Pontificia Universidad Católica del Ecuador, Quito, Ecuador; St George's University of London, London, United Kingdom.
authors.forename: Philip J
authors.initials: PJ
authors.lastname: Cooper
authors.affiliation: Laboratory of Parasitic Diseases, National Institutes of Health, Bethesda, Maryland, United States of America.
authors.forename: Cathy
authors.initials: C
authors.lastname: Steel
authors.affiliation: Laboratory of Parasitic Diseases, National Institutes of Health, Bethesda, Maryland, United States of America.
authors.forename: Thomas B
authors.initials: TB
authors.lastname: Nutman
authors.affiliation: Institute of Diabetes, Obesity, and Metabolism, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, United States of America.
authors.forename: Mitchell A
authors.initials: MA
authors.lastname: Lazar
authors.affiliation: Division of Biomedical Sciences, School of Medicine, University of California Riverside, Riverside, California, United States of America.
authors.forename: Meera G
authors.initials: MG
authors.lastname: Nair
mesh_terms: D000818:Animals; D016207:Cytokines / Q000378:metabolism; D005260:Female; D006373:Helminthiasis / Q000235:genetics / Q000276:immunology / Q000378:metabolism / Q000469:parasitology; D006801:Humans; D007249:Inflammation / Q000235:genetics / Q000276:immunology / Q000378:metabolism / Q000469:parasitology; D018836:Inflammation Mediators / Q000378:metabolism*; D008264:Macrophages / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009000:Monocytes / Q000276:immunology / Q000378:metabolism*; D009559:Nippostrongylus / Q000276:immunology; D018512:Parasitemia / Q000235:genetics* / Q000276:immunology / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D052243:Resistin / Q000235:genetics* / Q000378:metabolism; D017206:Strongylida Infections / Q000235:genetics / Q000276:immunology / Q000378:metabolism / Q000469:parasitology; D015854:Up-Regulation / Q000235:genetics
chemical_list: D016207:Cytokines; D018836:Inflammation Mediators; C499624:RETN protein, human; D052243:Resistin