RELMβ/FIZZ2 is a goblet cell-specific immune-effector molecule in the gastrointestinal tract

Abstract

Gastrointestinal (GI) nematode infections are an important public health and economic concern. Experimental studies have shown that resistance to infection requires CD4 ؉ T helper type 2 (Th2) cytokine responses characterized by the production of IL-4 and IL-13. However, despite >30 years of research, it is unclear how the immune system mediates the expulsion of worms from the GI tract. Here, we demonstrate that a recently described intestinal goblet cell-specific protein, RELM␤͞FIZZ2, is induced after exposure to three phylogenetically distinct GI nematode pathogens. Maximal expression of RELM␤ was coincident with the production of Th2 cytokines and host protective immunity, whereas production of the Th1 cytokine, IFN-␥, inhibited RELM␤ expression and led to chronic infection. Furthermore, whereas induction of RELM␤ was equivalent in nematode-infected wild-type and IL-4-deficient mice, IL-4 receptor-deficient mice showed minimal RELM␤ induction and developed persistent infections, demonstrating a direct role for IL-13 in optimal expression of RELM␤. Finally, we show that RELM␤ binds to components of the nematode chemosensory apparatus and inhibits chemotaxic function of a parasitic nematode in vitro. Together, these results suggest that intestinal goblet cell-derived RELM␤ may be a novel Th2 cytokine-induced immune-effector molecule in resistance to GI nematode infection.

A single-cell survey of the small intestinal epithelium

“…10b,c). There were also cell-intrinsic changes: within goblet cells, induction of genes previously implicated in anti-parasitic immunity 42 (FDR < 1×10 −5 , likelihood-ratio test; Extended Data Fig. 10d,e) some of which ( e.g.…”

“…During infection with H. polygyrus there was a striking increase in the number of goblet cells, known to respond to the parasite 42 , and a reduction in enterocytes (Fig. 6b).…”

Immunity to gastrointestinal nematode infections

“…[186][187][188] Resistin-like molecule-b (RELMb), in particular, prevents lumen-dwelling worms from feeding by effectively coating their cuticle, thus hampering growth as well as blocking motility and attachment to the host epithelium. 186,188 RELMb expression is highly increased in the intestinal epithelium during several parasite infections 186 (likely induced by ILC2) and is involved in the expulsion of H. polygyrus. 188 It might also be required for efficient expulsion of N. brasiliensis, although the data are conflicting.…”

The role of resistin as a regulator of inflammation: Implications for various human pathologies

“…It is involved in regulating intestinal homeostasis [124,125]. When secreted extracellularly, it can act as a regulatory molecule in luminal molecule recognition and transportation across the epithelial barrier and has been shown to bind to nematodes and to possess anti-chemotactic activity against the parasites.…”