Abstracts Category : Other

Human Resistin Regulates Immunity to Helminths and Sepsis

by Jessica Jang

Resistin-like molecules (RELM), a family of mammalian-conserved secreted proteins, have immunoregulatory effects in helminth infection, acting as a negative feedback loop to limit excess inflammation at the expense of increased parasite burden. This is through downregulation of the Th2 cytokines, IL-4 and IL-13, that are essential for alternative activation of macrophages and clearance of helminths. However, it is unclear how the human RELM proteins regulate immunity to helminth infections and inflammation. In this thesis, we have combine data from human studies and a transgenic mouse model, where human resistin and its regulatory region was inserted in mice (hRetnTg+). Human patients infected with filarial nematodes or soil-transmitted helminths had higher levels of circulating hResistin, and hResistin was associated with higher parasite burden. To assess whether hResistin directly increases helminth infection, we infected hRetnTg+ mice with the murine hookworm, Nippostrongylus brasiliensis (Nb), which revealed that hResistin is upregulated by macrophages and we identified IL-4/STAT6 signaling as a novel pathway for hResistin expression. Human resistin expression during helminth infection contributes to increased parasite burden and prolonged infection. RNA-seq of whole lung RNA demonstrated that hRetnTg+ mice had increase proinflammatory cytokines and toll-like receptor (TLR) signaling. In human patients infected with helminths, hResistin is correlated with proinflammatory cytokines, suggesting that hResistin contributes to increased helminth infection through the upregulation of Th1 cytokines. Structural interaction predictions revealed that hResistin binds to TLR4 in the same binding pocket as MD-2, the adaptor protein that mediates lipopolysaccharide(LPS)-TLR4 interaction. Given that LPS-TLR4 interaction initiates septic shock, we hypothesized that hResistin may protect the host from endotoxic shock by outcompeting LPS binding to TLR4 and blocking subsequent proinflammatory cytokine production. Competitive cell binding assays confirmed that hResistin does indeed outcompete LPS for binding to TLR4, and thereby decreases Th1 cytokines in human PBMC. In a mouse model of LPS-induced sepsis, hResistin expression or exogenous administration resulted in protection against endotoxic shock, which was associated with a decrease in proinflammatory cytokines that promote sepsis progression. Finally, we show that Nb-induced hResistin reduces mortality from sepsis. In summary, we have identified hResistin as a key regulator of inflammatory responses in helminth infections and sepsis.