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.

IntroductionMucosal surfaces, such as the intestine, are constantly exposed to the external environment, and development of a balanced immune response is essential to prevent pathogen invasion while controlling excessive or unnecessary inflammation. Notably, macrophages, which constitute a significant proportion of the leukocytes within the gut, serve as initiators to polarize immune effector or regulatory responses following a variety of infectious or inflammatory stimuli. RELMα is a secreted protein that is most commonly associated with alternatively activated macrophages (AAMac), which are recruited in T helper type (Th) 2 cytokine-dominated environments, such as helminth infection and allergy. [4][5][6] In Th2 cytokine-biased immune responses, RELMα exhibited critical immunomodulatory functions. [7][8][9] In contrast, studies by Rothenberg and colleagues uncovered a pro-inflammatory function for RELMα in mouse models of inflammatory bowel disease. 10,11 Our recent study focused on examining the role of RELMα in bacterial infection-induced inflammation.