THE ROLE OF IL-17RA- AND IL-17RC-DEPENDENT SIGNALS ON NON-HEMATOPOIETIC CELLS IN SHAPING THE HOST IMMUNE RESPONSES DURING CHLAMYDIA RESPIRATORY TRACT INFECTION

Abstract

The role of IL-17-family cytokines and their receptor-mediated signaling in host defense is complex. During my graduate study, I investigated the specific role of non-hematopoietic IL-17 receptor A (IL-17RA) and IL-17RC in controlling bacterial replication and host immune responses to intracellular Chlamydia infection in vitro and in vivo. A series of in vitro studies using mouse embryonic fibroblasts (MEFs) revealed that exogenous IL-17A, IL-17C, or IL-17E do not have inhibitory effects on intracellular Chlamydia replication in in MEFs. However, endogenous IL-17A is required to control Chlamydia replication as loss of IL-17RA in MEFs results in heightened bacterial burden. While Chlamydia infection stimulated production of cytokines and chemokines in MEFs, including IL-1α, IL-1β, IL-6, TNF, IL-10, IL-22, CXCL1, CCL3, CXCL2, TSLP, and GM-CSF, the cytokine profile was markedly altered in IL-17R-unresponsive MEFs, particularly in IL-17RA-knockout (KO) MEFs. In parallel with in vitro studies, bone marrow chimeric (BMC) mice were constructed using IL-17RAKO and IL-17RCKO mice as recipients for wild-type (WT) hematopoietic cells. Compared to WT-BMC mice, IL-17RAKO-BMC and IL-17RCKO-BMC mice displayed greater clinical disease upon respiratory Chlamydia infection, which was associated with significantly higher bacterial burden, enhanced rates of apoptosis, and heightened mononuclear cell infiltration in the lungs. A unique IL-17A-producing population with characteristic features of type 3 innate lymphoid cells (ILC3) was markedly induced in the BMC mice containing IL-17R-unresponsive tissue structure cells, particularly in IL-17RAKO-BMCs, indicating a relationship between IL-17RA and ILC3 induction in Chlamydia infection. Of interest, while IL-17RAKO-BMC mice displayed a type 17-biased immune profile, IL-17RCKO-BMC mice had enhanced type 1 immune responses compared to WT-BMC mice. Collectively, our results highlight an important role of non-hematopoietic IL-17RA and IL-17RC in host defense against Chlamydia infection and explicitly demonstrate distinct roles of IL-17RA and IL-17RC in tissue stromal cells in shaping host immune responses. To my knowledge, this is the first study in the Chlamydia research field that provides in-depth characterization of an animal model upon Chlamydia infection that will be useful in dissecting the nature of immunopathology associated with persistent Chlamydia infection.