CSF-1 receptor-mediated differentiation of a new type of monocytic cell with B cell-stimulating activity: its selective dependence on IL-34

Abstract

With the use of a mouse FDC line, FL-Y, we have been analyzing roles for FDCs in controlling B cell fate in GCs. Beside these regulatory functions, we fortuitously found that FL-Y cells induced a new type of CD11b⁺ monocytic cells (F4/80⁺, Gr-1⁻, Ly6C⁻, I-A/E(-/lo), CD11c⁻, CD115⁺, CXCR4⁺, CCR2⁺, CX₃CR1⁻) when cultured with a Lin⁻c-kit⁺ population from mouse spleen cells. The developed CD11b⁺ cells shared a similar gene-expression profile to mononuclear phagocytes and were designated as FDMCs. Here, we describe characteristic immunological functions and the induction mechanism of FDMCs. Proliferation of anti-CD40 antibody-stimulated B cells was markedly accelerated in the presence of FDMCs. In addition, the FDMC-activated B cells efficiently acquired GC B cell-associated markers (Fas and GL-7). We observed an increase of FDMC-like cells in mice after immunization. On the other hand, FL-Y cells were found to produce CSF-1 as well as IL-34, both of which are known to induce development of macrophages and monocytes by binding to the common receptor, CSF-1R, expressed on the progenitors. However, we show that FL-Y-derived IL-34, but not CSF-1, was selectively responsible for FDMC generation using neutralizing antibodies and RNAi. We also confirmed that FDMC generation was strictly dependent on CSF-1R. To our knowledge, a CSF-1R-mediated differentiation process that is intrinsically specific for IL-34 has not been reported. Our results provide new insights into understanding the diversity of IL-34 and CSF-1 signaling pathways through CSF-1R.

IL-34 and M-CSF form a novel heteromeric cytokine and regulate the M-CSF receptor activation and localization

“…In addition to the already identified functions of IL-34 and M-CSF in exacerbated macrophage activation (bowel diseases, liver fibrosis, chronic skin inflammation, arthritis, etc. ), this new heteromeric cytokine M-CSF/IL-34 which may differentially regulates the activation/localization of M-CSFR strengthens the global therapeutic approaches for blocking all biological functions coming from these molecules [7,8,[45][46][47][48][49][50][51].…”

CSF1 Overexpression Promotes High-Grade Glioma Formation without Impacting the Polarization Status of Glioma-Associated Microglia and Macrophages

“…Although CSF1 and IL-34 are both CSF1R ligands, they have been shown to activate biologically distinct signaling in vitro (31,32). Therefore, to identify the relevant CSF1R ligand(s) in human high-grade gliomas, mRNA expression array data at www.oncomine.org was mined.…”

Macrophage depletion ameliorates nephritis induced by pathogenic antibodies

“…Furthermore, the congenital absence of CSF-1 is not equivalent to inhibition of the CSF-1R. The CSF-1R has a second ligand, IL-34, which has unique roles in the regulation of monocyte/macrophage populations [37]. Thus, in the CSF-1 or CSF-1R knockout strains reported previously, nephritis may have been attenuated because it developed on an altered background, preventing the conclusive determination of the therapeutic efficacy of suppressing CSF-1R in lupus.…”