Cardiotrophin-like Cytokine Increases Macrophage–Foam Cell Transition

Abstract

CLCF1 is a neurotrophic and B cell-stimulating factor belonging to the IL-6 family. Mutations in the gene coding for CLCF1 or its secretion partner CRLF1 lead to the development of severe phenotypes, suggesting important nonredundant roles in development, metabolism, and immunity. Although CLCF1 was shown to promote the proliferation of the myeloid cell line M1, its roles on myeloid activation remain underinvestigated. We characterized the effects of CLCF1 on myeloid cells with a focus on monocyte-macrophage and macrophage-foam cell differentiations. CLCF1 injections in mice resulted in a significant increase in CD11b circulating cells, including proinflammatory monocytes. Furthermore, CLCF1 activated STAT3 phosphorylation in bone marrow CD11b cells and in bone marrow-derived macrophages (BMDM). BMDM stimulated with CLCF1 produced a large array of proinflammatory factors comprising IL-6, IL-9, G-CSF, GM-CSF, IL-1β, IL-12, CCL5, and CX3CL1. The pattern of cytokines and chemokines released by CLCF1-treated BMDM led us to investigate the role of CLCF1 in foam cell formation. When pretreated with CLCF1, BMDM presented a marked SR-A1 upregulation, an increase in acetylated-low-density lipoprotein uptake, and an elevated triglyceride accumulation. CLCF1-induced SR-A1 upregulation, triglyceride accumulation, and acetylated-low-density lipoprotein uptake could be prevented using ruxolitinib, a JAK inhibitor, indicating that the effects of the cytokine on myeloid cells result from activation of the canonical JAK/STAT signaling pathway. Our data reveal novel biological roles for CLCF1 in the control of myeloid function and identify this cytokine as a strong inducer of macrophage-foam cell transition, thus bringing forward a new potential therapeutic target for atherosclerosis.

Cardiotrophin-like cytokine (CLCF1) modulates mesenchymal stem cell osteoblastic differentiation

“…is required for hematopoietic stem cell maintenance (33), a role that could involve bone marrow stromal cells, such as MSCs. CLCF1 administration was shown to promote B cell expansion and myelopoiesis (2,34,35). Ligands of CNTFR are believed to have direct and indirect effects on hematopoietic cells, such as B cells (2, 34 -36).…”

Engineering a potent receptor superagonist or antagonist from a novel IL-6 family cytokine ligand

“…CLCF1 is underexplored in comparison to CNTF but is highly prominent in lung adenocarcinoma, where it is secreted by cancer cells and cancer-associated fibroblasts to promote tumor through both autocrine and paracrine signaling (23,24). Furthermore, CLCF1 has also recently been shown to play a role in osteoporosis (25) and atherosclerosis (26). These studies highlight CNTFR and its ligands as targets for therapeutic intervention; a CNTFR agonist could potentially facilitate neuronal regeneration, while a CNTFR antagonist could inhibit this signaling axis for cancer or other disease treatment.…”

CLCF1 is up-regulated in renal ischemia reperfusion injury and may associate with FOXO3

“…The function of CLCF1 remains far from being understood. Recent studies have indicated that CLCF1 attend to modulate mesenchymal stem cell osteoblastic differentiation (26) and promote macrophage-foam cell transition (27). For kidney diseases, CLCF1 has been reported to trigger the recurrence of FSGS after kidney transplantation (12).…”