Interleukin-25-mediated resistance against intestinal trematodes does not depend on the generation of Th2 responses

Abstract

Background The cytokine interleukin-25 (IL-25) is recognized as the most relevant initiator of protective T helper 2 (Th2) responses in intestinal helminth infections. This cytokine induces resistance against several species of intestinal helminths, including the trematode Echinostoma caproni. E. caproni has been extensively used as an experimental model to study the factors determining resistance to intestinal infections. In the study reported here, we assessed the role of IL-25 in the generation of resistance in mice infected with E. caproni. Methods The factors that determine the production of IL-25 in mice experimentally infected with E. caproni were determined, as were the consequences of IL-25 production in terms of polarization of the immune response and resistance to infection. Results Our results show that the role of IL-25 in the polarization of the immune response differs between the primary and secondary immune responses. IL-25 is required for the development of a Th2 phenotype in primary E. caproni infections, but it can also promote the differentiation to Th2 memory cell subsets that enhance type-2 immunity in memory responses. However, the development of Th2 responses does not induce resistance to infection. The Th2 phenotype does not elicit resistance, and IL-25 is responsible for the resistance regardless of its type-2 cytokine activity and activation of signal transducer and activator of transcription (STAT6). Alternative activation of macrophages induced by IL-25 can be implicated in the resistance to infection. Conclusions In contrast to primary infection, secondary infection elicits a type-2 immune response even in the absence of IL-25 expression. Despite the development of a type-2 response, mice are susceptible to secondary infection associated with the lack of IL-25. Resistance to infection is due to the production of IL-25, which acts autonomously from Th2 response in terms of parasite clearance.

Enteric Tuft Cells in Host-Parasite Interactions

“…In E. caproni-infected mice, ETC hyperplasia was observed during a chronic, Th1-inducing primary infection, with no concurrent increase in the intestinal levels of IL-25 [10,53]. Upon secondary infection with E. caproni (i.e., post-drug clearance of the primary infection) both ETC hyperplasia as well as an increase in tissue IL-25 levels were observed alongside worm clearance (Figure 2) [10,63]. The mode by which IL-25 is stimulated during secondary protection remains unknown [10,63], however there was also increased expression of IL-13 [63].…”

“…Whether ETCs respond to the protozoans Cryptosporidium and Entamoeba remains to be tested even though host resistance in both cases are characterized by Th1 dominant responses [61,62]. Recent discoveries also encourage discussion around ETC functions beyond mobilization of anti-worm responses, such as tissue repair and protection from secondary infections [6,7,9,10,50,57,58,63], and provide additional rationale to study ETC responses to enteric parasites that infect humans and livestock. In response to helminths and protozoans, ETCs produce and release IL-25 (1-4) and cysteinyl leukotrienes (1,2), which subsequently activate the innate lymphoid cell (ILC2) population in the underlying lamina propria via IL-17RB and CYSLTR receptors to produce IL-13, IL-5 and IL-9 [6,7,9,57,64].…”

“…ILC2s also produce and release acetylcholine (ACh) in response to infection with N. brasileinsis and are activated by ACh to produce IL-13 (2) [65,66]. Although ETC hyperplasia is observed after primary and secondary infection with E. caproni, Il-25 expression is upregulated in the acute secondary infection rather than the chronic primary infection, which is characterized by increased levels of Th1 cytokine mRNA (5) [10,53,63]. ETC-derived mediators may also act on other cell types such as eosinophils and macrophages (alternatively activated macrophages, AAM), to coordinate repair, as well activate CD4 T cell populations (4,5) to release cytokines during parasitic infections [48,[67][68][69]."?"…”

“…Upon secondary infection with E. caproni (i.e., post-drug clearance of the primary infection) both ETC hyperplasia as well as an increase in tissue IL-25 levels were observed alongside worm clearance (Figure 2) [10,63]. The mode by which IL-25 is stimulated during secondary protection remains unknown [10,63], however there was also increased expression of IL-13 [63].…”

Interleukin 25 and its biological features and function in intestinal diseases

“…also suggested that IL-25 is unable to impact the differentiation of Th2 cells and their development into effector or memory Th2 cells [ 33 ]. However, several studies have offered evidence that IL-25 may impact Th2 memory cells [ 34 , 35 ].…”