Macrophage-Derived Human Resistin Is Induced in Multiple Helminth Infections and Promotes Inflammatory Monocytes and Increased Parasite Burden

PLoS Pathogens

Cathy Steel¹  Spencer H. Wang²  Josiah I. Chung²  Jessica C. Jang²  Gang Chen²  Mark A. Barnes²  Philip J. Cooper³  Meera G. Nair⁴  Mitchell A. Lazar⁴  Mali Camberis⁵  Graham Le Gros⁵  Thomas B. Nutman⁶ 

[1] Centro de Investigación en Enfermedades Infecciosas, Pontificia Universidad Católica del Ecuador, Quito, Ecuador;Division of Biomedical Sciences, School of Medicine, University of California Riverside, Riverside, California, United States of America;Laboratorio de Investigaciones FEPIS, Quinindé, Ecuador;Laboratory of Parasitic Diseases, National Institutes of Health, Bethesda, Maryland, United States of America;Malaghan Institute of Medical Research, Wellington, New Zealand;St George's University of London, London, United Kingdom

关键词: Resistin;    Helminth infections;    Cytokines;    Monocytes;    Inflammation;    Nematode infections;    Parasitic diseases;    Mouse models;   

DOI  :  10.1371/journal.ppat.1004579

学科分类：生物科学（综合）

来源: Public Library of Science

【 摘 要 】

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.

【 授权许可】

CC BY