Macrophage-derived human resistin is induced in multiple helminth infections and promotes inflammatory monocytes and increased parasite burden
| Autor: | Mark A. Barnes, Graham Le Gros, Philip J. Cooper, Spencer H. Wang, Cathy Steel, Mitchell A. Lazar, Jessica C. Jang, Josiah I. Chung, Mali Camberis, Meera G. Nair, Gang Chen, Thomas B. Nutman |
|---|---|
| Přispěvatelé: | Pearce, Edward J |
| Rok vydání: | 2015 |
| Předmět: |
Male
parasitology Helminthiasis Parasitemia Inbred C57BL Parasite load Monocytes Transgenic Rats Sprague-Dawley Mice 0302 clinical medicine immunology [Nippostrongylus] Medicine and Health Sciences 2.1 Biological and endogenous factors Resistin Nippostrongylus brasiliensis Biology (General) Aetiology Lung 0303 health sciences biology genetics [Resistin] 3. Good health Up-Regulation medicine.anatomical_structure Infectious Diseases Medical Microbiology genetics [Up-Regulation] Cytokines Female Nippostrongylus medicine.symptom Inflammation Mediators Infection Research Article QH301-705.5 Immunology genetics [Helminthiasis] Inflammation Mice Transgenic Microbiology Proinflammatory cytokine 03 medical and health sciences genetics [Inflammation] immunology [Monocytes] Immune system Rare Diseases Virology genetics [Strongylida Infections] parasitic diseases Genetics medicine Parasitic Diseases Animals Humans Molecular Biology genetics [Parasitemia] 030304 developmental biology Strongylida Infections Monocyte Inflammatory and immune system Macrophages metabolism [Inflammation Mediators] Biology and Life Sciences metabolism [Cytokines] RC581-607 biology.organism_classification medicine.disease Rats Mice Inbred C57BL Vector-Borne Diseases metabolism [Macrophages] Parasitology Sprague-Dawley Immunologic diseases. Allergy Digestive Diseases metabolism 030215 immunology |
| Zdroj: | PLoS pathogens, vol 11, iss 1 PLoS Pathogens PLoS Pathogens, Vol 11, Iss 1, p e1004579 (2015) |
| ISSN: | 1553-7374 |
| Popis: | 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. Author Summary Parasitic helminths, which infect an estimated two billion people worldwide, represent a significant global public health problem. Infection is associated with life-long morbidity including growth retardation and organ failure. Despite these debilitating conditions, there are currently no successful vaccines against helminths. Further, great variability in the host immune response to helminths exists, with the ability of some individuals to develop immunity, while others are susceptible when re-exposed or maintain life-long chronic infections. Identifying new factors that are differentially expressed in immune versus susceptible individuals could provide new targeting strategies for diagnosis or treatment of helminth infection. Here, we identify an important immunoregulatory function for human resistin in helminth infection. Employing transgenic mice in which the human resistin gene was inserted, we show that human resistin is induced by infection with the helminth Nippostrongylus brasiliensis, where it promotes excessive inflammation and impedes parasite killing. Moreover, analysis of clinical samples from two cohorts of individuals infected with filarial nematodes or soil-transmitted helminths revealed increased resistin and serum proinflammatory cytokines compared to putatively immune individuals. Together, these studies suggest that human resistin is a detrimental cytokine that is expressed in multiple helminth infections, mediates pathogenic inflammation, and delays parasite clearance. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|