Highlights d Blood cell traits differ by ancestry and are subject to selective pressure d We assessed 15 blood cell traits in 746,667 participants from 5 global populations d We identified more than 5,500 associations, including 100 associations not found in Europeans d These analyses improved risk prediction and identified potential causal variants
Mesenchymal stem cells (MSCs) are multipotent cells capable of differentiating into adipocytes, chondrocytes, or osteocytes. MSCs secrete an array of cytokines and express the LIFR (leukemia inhibitory factor receptor) chain on their surface. Mutations in the gene coding for LIFR lead to a syndrome with altered bone metabolism. LIFR is one of the signaling receptor chains for cardiotrophin-like cytokine (CLCF1), a neurotrophic factor known to modulate B and myeloid cell functions. We investigated its effect on MSCs induced to differentiate into osteocytes in vitro. Our results indicate that CLCF1 binds mouse MSCs, triggers STAT1 and-3 phosphorylation, inhibits the upregulation of master genes involved in the control of osteogenesis, and markedly prevents osteoblast generation and mineralization. This suggests that CLCF1 could be a target for therapeutic intervention with agents such as cytokine traps or blocking mAbs in bone diseases such as osteoporosis.
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 factor 1 (CLCF1) is secreted as a complex with the cytokine receptor-like factor 1 (CRLF1). Syndromes caused by mutations in the genes encoding CLCF1 or CRLF1 suggest an important role for CLCF1 in the development and regulation of the immune system. In mice, CLCF1 induces B-cell expansion, enhances humoral responses and triggers autoimmunity. Interestingly, inactivation of CRLF1, which impedes CLCF1 secretion, leads to a marked reduction in the number of bone marrow (BM) progenitor cells, while mice heterozygous for CLCF1 display a significant decrease in their circulating leukocytes. We therefore hypothesized that CLCF1 might be implicated in the regulation of hematopoiesis. To test this hypothesis, murine hematopoietic progenitor cells defined as Lin−Sca1+c-kit+ (LSK) were treated in vitro with ascending doses of CLCF1. The frequency and counts of LSK cells were significantly increased in the presence of CLCF1, which may be mediated by several CLCF1-induced soluble factors including IL-6, G-CSF, IL-1β, IL-10, and VEGF. CLCF1 administration to non-diseased C57BL/6 mice resulted in a pronounced increase in circulating myeloid cells, which was concomitant with augmented LSK and myeloid cell counts in the BM. Likewise, CLCF1 administration to mice following sub-lethal irradiation or congeneic BM transplantation (BMT) resulted in accelerated LSK recovery along with a sustained increase in BM-derived CD11b+ cells. Altogether, our observations establish an important and unforeseen role for CLCF1 in regulating hematopoiesis with a bias toward myeloid cell differentiation.
Cardiotrophin-like Cytokine Factor 1 (CLCF1) belongs to the IL6 family of cytokines and possesses pro-neurotrophic and immuno-modulating functions. Coding mRNA for CLCF1 has been detected in primary and secondary lymphoid organs (i.e. lymph nodes, spleen and bone marrow), as well as in the lungs and feminine reproductive organs. Modulation of CLCF1’s mRNA levels has been associated with the Th17 polarization in CD4+ T cells. However, little information is available regarding CLCF1 protein levels in these tissues or the nature of the immune cells responsible for its production. This can be explained by a lack of in situ detection options for CLCF1. We have therefore developed a methodology for the detection of human and murine CLCF1 by flow cytometry in permeabilized cells. This technique has been validated using derivatives of the Ba/F3 cell line in which cDNAs coding for human and murine CLCF1 were introduced by transduction with recombinant retroviruses. We are currently using this approach to study CLCF1 production by human and murine immune cells. Preliminary results indicate a production of CLCF1 by Th17 T cells. The development of a method to detect CLCF1 by flow cytometry will be beneficial for the study of CLCF1’s functions in the regulation of the immune response.
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