DCIR suppresses osteoclastic proliferation and resorption by downregulating M-CSF and RANKL signaling

Tomonori Kaifu; Takumi Maruhashi; Soo-Hyun Chung; Kenji Shimizu; Akira Nakamura; Yoichiro Iwakura

doi:10.3389/fimmu.2023.1159058

DCIR suppresses osteoclastic proliferation and resorption by downregulating M-CSF and RANKL signaling

Front Immunol. 2023 May 17:14:1159058. doi: 10.3389/fimmu.2023.1159058. eCollection 2023.

Authors

Tomonori Kaifu¹, Takumi Maruhashi², Soo-Hyun Chung³, Kenji Shimizu², Akira Nakamura¹, Yoichiro Iwakura³

Affiliations

¹ Division of Immunology, Faculty of Medicine, Tohoku Medical and Pharmaceutical University, Sendai, Miyagi, Japan.
² Laboratory of Molecular Immunology, Institute for Quantitative Biosciences, The University of Tokyo, Tokyo, Japan.
³ Center for Animal Disease Models, Research Institution for Biological Sciences, Tokyo University of Science, Noda, Chiba, Japan.

Abstract

Dendritic cell immunoreceptor (DCIR) is an inhibitory C-type lectin receptor that acts as a negative regulator in the immune system and bone metabolism. We previously revealed that DCIR deficiency enhanced osteoclastogenesis and antigen presentation of dendritic cells, and that asialo-biantennary N-glycan (NA2) functions as a ligand for DCIR. NA2 binding to DCIR suppressed murine and human osteoclastogenesis that occurs in the presence of M-CSF and RANKL. The DCIR-NA2 axis, therefore, plays an important role in regulating osteoclastogenesis in both mice and humans, although the underlying mechanisms remain unclear. Here we found that Dcir ^-/- bone marrow-derived macrophages (BMMs) exhibited greater proliferative and differentiation responses to M-CSF and RANKL, respectively, than wild-type (WT) BMMs. Moreover, Dcir ^-/- osteoclasts (OCs) increased resorptive activity and cell fusion more significantly than WT OCs. DCIR deficiency affects gene expression patterns in OCs, and we found that the expression of neuraminidase 4 was increased in Dcir ^-/- OCs. Furthermore, DCIR-NA2 interaction in WT BMMs, but not Dcir ^-/- BMMs, decreased Akt phosphorylation in response to M-CSF and RANKL. These data suggest that DCIR regulates osteoclastogenesis by downregulating M-CSF and RANKL signaling, and that DCIR-mediated signaling may contribute to the terminal modification of oligosaccharides by controlling the expression of glycosylation enzymes.

Keywords: C-type lectin receptor; DCIR; cytokines; homeostasis; metabolism; oligosaccharides; osteoclast.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Bone Resorption* / metabolism
Cell Proliferation
Humans
Macrophage Colony-Stimulating Factor* / metabolism
Macrophage Colony-Stimulating Factor* / pharmacology
Mice
Osteoclasts / metabolism
Signal Transduction

Substances

Macrophage Colony-Stimulating Factor
Dcir protein, mouse
CLEC4A protein, human

Grants and funding

This work was supported in part by a grant from the Core Research for Evolutionary Science and Technology (CREST) program of the Japan Science and Technology Agency (JST) (Grant Number, 105100000222), a Grant-in-Aid for Scientific Research (S) (24220011) from the Japan Society for the Promotion of Science (JSPS), and a grant from the Japan Agency for Medical Research and Development (AMED) (16809407), all to YI, as well as by a Grant-in-Aid for Scientific Research (C) (Grant Number, 23500489) from JSPS to TK.