Critical Role of IL-25 in Nematode Infection-Induced Alterations in Intestinal Function

Abstract

IL-25 (IL-17E) is a member of the IL-17 cytokine family. IL-25–deficient mice exhibit impaired Th2 immunity against nematode infection, implicating IL-25 as a key component in mucosal immunity. The sources of IL-25 and mechanisms responsible for the induction of Th2 immunity by IL-25 in the gastrointestinal tract remain poorly understood. There is also little information on the regulation of IL-25 during inflammation or its role in gut function. In the current study, we investigated the regulation of IL-25 during Nippostrongylus brasiliensis infection and the contribution of IL-25 to the infection-induced alterations in intestinal function. We found that epithelial cells, but not immune cells, are the major source of IL-25 in the small intestine. N. brasiliensis infection-induced upregulation of IL-25 depends upon IL-13 activation of STAT6. IL-25−/− mice had diminished intestinal smooth muscle and epithelial responses to N. brasiliensis infection that were associated with an impaired Th2 protective immunity. Exogenous IL-25 induced characteristic changes similar to those after nematode infection but was unable to restore the impaired host immunity against N. brasiliensis infection in IL-13−/− mice. These data show that IL-25 plays a critical role in nematode infection-induced alterations in intestinal function that are important for host protective immunity, and IL-13 is the major downstream Th2 cytokine responsible for the IL-25 effects.

Genetic, immunological, and clinical features of patients with bacterial and fungal infections due to inherited IL-17RA deficiency

“…Unlike those of IL-17RC-deficient patients, PBMCs from ACT1-deficient and IL-17RA-deficient patients do not respond to IL-17E/IL-25 (10,11). The role of human IL-17E/IL-25 is unknown, in the absence of known patients bearing specific mutations, but its mouse counterpart is known to promote "Th2"-mediated responses (89,90) and to be involved in immunity to parasitic infections (91)(92)(93). We were unable to detect cellular responses to IL-17B, -17D, and even -17C (83) in control fibroblasts, keratinocytes, or leukocytes.…”

Immunity to gastrointestinal nematode infections

“…191 Intestinal peristalsis is mediated by contraction of smooth muscle cells, and is induced by both IL-9 (ref. 102), IL-4 and IL-13, 27,73,192 and seems to be controlled mainly by T cells. Thus, the responsiveness of smooth muscle cells to neurotransmitters that control contraction via muscarinic receptors are important for N. brasiliensis expulsion.…”

“…[15][16][17]25,[34][35][36][37][38] Epithelium-derived IL-25 and IL-33, in particular, are important for driving IL-5 and IL-13 production from ILC2, the latter of which induces a number of responses, including goblet and tuft cell expansion, resulting in a strong positive feedback loop with increased production of IL-25 by epithelial cells. [15][16][17]31,[34][35][36][37] As a consequence, mice lacking IL-25 have less efficient expulsion of T. muris, 26 T. spiralis, 39 N. brasiliensis, 25,27,40 and H. polygyrus 28 worms. Furthermore, exogenous administration of IL-25 fails to restore expulsion in il13 À / À mice, 25,27 whereas the reverse is true, 15,17 illustrating that IL-25 acts upstream of IL-13 rather than directly on expulsion.…”

“…[15][16][17]31,[34][35][36][37] As a consequence, mice lacking IL-25 have less efficient expulsion of T. muris, 26 T. spiralis, 39 N. brasiliensis, 25,27,40 and H. polygyrus 28 worms. Furthermore, exogenous administration of IL-25 fails to restore expulsion in il13 À / À mice, 25,27 whereas the reverse is true, 15,17 illustrating that IL-25 acts upstream of IL-13 rather than directly on expulsion. Strikingly, exogenous administration of IL-25 in the early stages of N. brasiliensis infection results in worm clearance in both wild-type and rag1 -/-mice, 25 strongly suggesting that at high enough concentrations of IL-25, ILC2 activation can overcome T-and B-cell deficiency (which normally is associated with chronicity).…”

The roles and functional mechanisms of interleukin-17 family cytokines in mucosal immunity

“…Another study showed that epithelial-derived IL-17E was critical for Nippostrongylus brasiliensis expulsion from the intestine. 139 Although many ILC2s (that is, MPP type2 cells, nuocytes and Ih2 cells) can promote type 2 immunity in response to IL-17E, the precise roles of IL-17E and these ILC2s in worm expulsion need to be determined in the future. 9 Exogenous delivery of IL-17E also protects mice from Trichuris muris infection, whereas IL-17E deficiency in mice leads to impaired worm clearance.…”