The human protein resistin drives detrimental inflammatory monocyte responses in helminth infection (MPF7P.710)

Resistin-like molecules (RELM) belong to a family of secreted proteins that are expressed in multiple helminth infections with important effects on the host immune response. However the importance of human RELM proteins in helminth infections is less well understood. To investigate this, we utilized transgenic mice that expressed the human resistin gene (Tg+). Following infection with Nippostrongylus brasiliensis , a hookworm that colonizes the lung and intestine, Tg+ mice exhibited significant lung inflammation, characterized by increased inflammatory monocytes and elevated parasite burdens compared to control Tg- mice. Genome-wide transcriptional profiling of the infected lung tissue from Tg+ and Tg- mice revealed that genes associated with cytokine and TLR signaling were significantly elevated in Tg+ mice. To delineate the downstream cellular mediators of resistin, we performed a resistin binding and chemotaxis assay and identified monocytes as the main cell-types that were responsive to resistin. Moreover, monocytes sorted from the infected lung tissue of Tg+ mice expressed significantly higher TNFα compared to Tg- mice. In human studies, increased serum resistin was associated with higher helminth burdens and was positively correlated with inflammatory cytokines. Together, these studies identify a detrimental role for human resistin in instigating a non-protective inflammatory response that may be mediated by monocytes.