Intestinal epithelial cell secretion of RELM-β protects against gastrointestinal worm infection

Abstract

Th2 cells drive protective immunity against most parasitic helminths, but few mechanisms have been demonstrated that facilitate pathogen clearance. We show that IL-4 and IL-13 protect against intestinal lumen-dwelling worms primarily by inducing intestinal epithelial cells (IECs) to differentiate into goblet cells that secrete resistin-like molecule (RELM) β. RELM-β is essential for normal spontaneous expulsion and IL-4–induced expulsion of Nippostrongylus brasiliensis and Heligmosomoides polygyrus, which both live in the intestinal lumen, but it does not contribute to immunity against Trichinella spiralis, which lives within IEC. RELM-β is nontoxic for H. polygyrus in vitro but directly inhibits the ability of worms to feed on host tissues during infection. This decreases H. polygyrus adenosine triphosphate content and fecundity. Importantly, RELM-β–driven immunity does not require T or B cells, alternative macrophage activation, or increased gut permeability. Thus, we demonstrate a novel mechanism for host protection at the mucosal interface that explains how stimulation of epithelial cells by IL-4 and IL-13 contributes to protection against parasitic helminthes that dwell in the intestinal lumen.

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.…”

“…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. 188,189 In contrast, there seems to be no role for RELMb in the expulsion of T. spiralis or T. muris.…”

“…188 It might also be required for efficient expulsion of N. brasiliensis, although the data are conflicting. 188,189 In contrast, there seems to be no role for RELMb in the expulsion of T. spiralis or T. muris. 187,188 RELMa, on the other hand, is mainly expressed in the pulmonary epithelium and might be important for combating the pulmonary stage of N. brasiliensis.…”

A sticky end for gastrointestinal helminths; the role of the mucus barrier

“…However, it is important to note that as the intestinal tract is such a dynamic and exposed tissue, it is also likely that the mucus gel will contain exfoliated cells from the rapidly turned over epithelial layer, bacterial‐derived products and dietary components, making it difficult to extrapolate which proteins are functionally important. However, proteins with a structural, antimicrobial and regulatory function have been associated with the mucus gel and have been identified to be present during parasitic infection 87, 88, 89, 90, 91. Several nonmucin proteins have also been demonstrated to be present within goblet cell granules within the intestine, including IgG Fc‐gamma‐binding protein (FCGBP), trefoil factor (TTF), chloride channel regulator calcium‐activated‐1 (CLCA1), resistin‐like molecule (RELM)‐β and ZG16,87, 92, 93, 94 but relatively few have been investigated during GI nematode infection.…”

“…It has been proposed that RELM‐β can affect the ATP levels and hence the fitness of H. polygyrus and N. brasiliensis through impairing the parasites ability to feed. Moreover, RELM‐β can aid host protection against N. brasiliensis by causing entrapment of the parasite and reducing parasite motility 88. However, during T. muris and T. spiralis infection there is an induction of RELM‐β expression, but it appears to play little role in expulsion 87.…”