Caractérisation des fonctions immunomodulatrices de la Cardiotrophin-Like Cytokine
Cardiotrophin-Like Cytokine (CLCF1) is a cytokine of the IL-6 family recognized primarily for its neurotrophic functions mediated by CNTF receptor activation (CNTFR). In contrast to its counterpart CNTF, CLCF1 is efficiently secreted as a composite cytokine with the soluble receptor CRLF1. Mutations in the genes encoding for CLCF1 or its secretion partner CRLF1 lead to the development of CISS and Crisponi syndromes, two severe conditions associated with complex overlapping phenotypes. Studying patients’ phenotypes led us to hypothesize important, non-redundant CLCF1 functions in the development and regulation of the immune system.  To characterize the immunomodulatory properties of this cytokine, we first studied the roles of CLCF1 in hematopoiesis. We observed that CLCF1 stimulates the proliferation of multipotent hematopoietic cells and induces their expansion in absence of other growth factors. In vivo, administration of the cytokine accelerated myeloid cell reconstitution in a model of congenic bone marrow transplantation. These results therefore suggest yet-unidentified roles for CLCF1 in myelopoiesis regulation. In a subsequent study, we assessed the ability of CLCF1 to modulate myeloid cell activation. Assessing the impact of CLCF1 on macrophages functions and differentiation, we determined that CLCF1 1) activates JAK/STAT signaling pathways in bone marrow-derived macrophages (BMDM), 2) induces the upregulation of scavenger receptor SR-A1 expression and 3) promotes the formation of pro-atherogenic foam cells. Altogether, these results indicate that CLCF1 may constitute a novel and attractive therapeutic target to be investigated in preclinical models of atherosclerosis. While CLCF1 has previously been recognized as a B-cell stimulating factor, the results presented in the first two articles of this thesis indicate biological functions for CLCF1 in the formation and regulation of myeloid cells.  In parallel, we defined new biochemical interactions between CLCF1 and plasma lipoproteins. In particular, we have demonstrated the existence of complexes between CLCF1, apolipoprotein E, low- and very low-density lipoproteins. Furthermore, we observed that CLCF1 biological activities are modulated by very low-density lipoproteins. These results provide evidence of direct interactions between lipoproteins and cytokines and suggest that certain metabolic components modulate the immune functions of type I cytokines.  In conclusion, the results summarized in this thesis have improved our understanding of CLCF1 immunomodulatory properties and of its potential therapeutic applications.
Cardiotrophin-Like Cytokine Cytokine IL-6 Macrophage Cardiotrophin-Like Cytokine Hematopoiesis Hematopoietic Stem Cell Myeloid Cells Atherosclerosis Apolipoprotein E Lipoprotein