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

Abstract Interleukin-25 (IL-25) is recognized as the most relevant initiator of protective Th2 responses in intestinal helminth infections. It is well known that IL-25 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 the resistance to intestinal infections. Herein, we assessed the role of IL-25 in the generation of resistance in mice to E. caproni infections. ICR mice are permissive hosts for E. caproni in which chronic infections are developed in relation to the lack of IL-25 production in response to primary infection and the consequent development of a Th1 response. However, pharmacological clearance of the primary infection induces non-specific expression of IL-25 that protects mice to secondary challenge infections in association with Th2 responses. Using this experimental model, we have determined that the role of IL-25 in the polarization of the immune response differs between the primary and secondary memory response. IL-25 is required for the development of a Th2 phenotype in primary E. caproni infections but also promotes the differentiation to Th2 memory cell subsets that enhances type 2 responses in memory responses, even in the absence of IL-25. Despite these events, development of Th2 responses does not induce resistance to infection. Our results suggest that Th2 phenotype does not elicit resistance and IL-25 is responsible for the resistance regardless of the type 2 cytokine activity and STAT6 activation. Alternative activation of macrophages induced by IL-25 could be implicated in the resistance to infection. In view of the critical role of IL-25, we have also investigated the factors determining the production of IL-25 and appears to be related to the alterations in resident microbiota induced by the infection. Author’s summary Interleukin-25 (IL-25) plays a major role in resistance against intestinal helminth infections as initiator of protective Th2 responses. However, recent studies have challenged the contribution of this cytokine in both the polarization of the response towards a Th2 phenotype and the parasite rejection. We have used the experimental model Echinostoma caproni -ICR mice to investigate the participation of this cytokine in resistance to intestinal helminths. ICR mice are characterized by their inability to respond with IL-25 production in primary infections with E. caproni , causing susceptibility associated with a Th1 response. However, mice are refractory to infection in presence of IL-25 in relation to a type 2 phenotype. Herein, we show that dynamics of resident microbiota appears to be crucial in IL-25 production. Moreover, IL-25 seems to play a pivotal role in the polarization to Th2 in primary responses, but also appears to participate in the generation of memory mechanisms making unnecessary the participation of IL-25 in memory responses for the development of Th2 milieu. However, resistance to E. caproni infection does not depend on the generation of a Th2 phenotype, but exclusively depends on the presence of IL-25, operating autonomously from the type 2 response in the generation of resistance.