Inhibitory immunoglobulin-like receptors LILRB and PIR-B negatively regulate osteoclast development.
Osteoclasts, multinucleated cells of myeloid-monocytic origin, are responsible for bone resorption, which is crucial for maintenance of bone homeostasis in concert with bone-forming osteoblasts of nonhematopoietic, mesenchymal origin. Receptor activator of NF-kappaB ligand (RANKL) and M-CSF, expressed on the surface of and secreted by osteoblasts, respectively, are essential factors that facilitate osteoclast formation. In contrast to the activation processes for osteoclast formation, inhibitory mechanisms for it are poorly understood. Herein we demonstrate that inhibitory Ig-like receptors recruiting Src homology 2 domain-containing tyrosine phosphatase 1 (SHP-1) are expressed on osteoclast precursor cells like other myeloid cells, and that they play a regulatory role in the development of osteoclasts. We detected cell-surface expression of paired Ig-like receptor (PIR)-B and four isoforms of leukocyte Ig-like receptor (LILR)B on cultured osteoclast precursor cells of mouse and human origin, respectively, and showed that all of these ITIM-harboring inhibitory receptors constitutively recruit SHP-1 in the presence of RANKL and M-CSF, and that some of them can suppress osteoclast development in vitro. Fluorescence energy transfer analyses have suggested that the constitutive binding of either murine PIR-B or its human ortholog LILRB1 to MHC class I molecules on the same cell surface comprises one of the mechanisms for developmental regulation. These results constitute the first evidence of the regulation of osteoclast formation by cell-surface, ITIM-harboring Ig-like receptors. Modulation of these regulatory receptors may be a novel way to control various skeletal system disorders and inflammatory arthritis.
Mori
Yu
Y
Department of Experimental Immunology, Institute of Development, Aging, and Cancer, and Center of Excellence Program for Innovative Therapeutic Development Towards the Conquest of Signal Transduction Diseases, Tohoku University, Sendai, Japan.
Tsuji
Sukenao
S
Inui
Masanori
M
Sakamoto
Yuzuru
Y
Endo
Shota
S
Ito
Yumi
Y
Fujimura
Shion
S
Koga
Takako
T
Nakamura
Akira
A
Takayanagi
Hiroshi
H
Itoi
Eiji
E
Takai
Toshiyuki
T
D000818:Animals; D015703:Antigens, CD / Q000096:biosynthesis / Q000097:blood / Q000502:physiology*; D001854:Bone Marrow Cells / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D002454:Cell Differentiation / Q000235:genetics / Q000276:immunology*; D002478:Cells, Cultured; D006131:Growth Inhibitors / Q000502:physiology*; D006801:Humans; D000075362:Leukocyte Immunoglobulin-like Receptor B1; D016173:Macrophage Colony-Stimulating Factor / Q000502:physiology; D008562:Membrane Glycoproteins / Q000096:biosynthesis / Q000097:blood / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D055017:Monocyte-Macrophage Precursor Cells / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D010006:Osteoblasts / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D010010:Osteoclasts / Q000166:cytology / Q000276:immunology* / Q000378:metabolism; D010024:Osteoporosis / Q000235:genetics / Q000276:immunology / Q000473:pathology; D020033:Protein Isoforms / Q000096:biosynthesis / Q000097:blood / Q000502:physiology; D053245:RANK Ligand / Q000502:physiology; D011956:Receptors, Cell Surface / Q000096:biosynthesis / Q000097:blood / Q000502:physiology*; D011961:Receptors, Fc / Q000096:biosynthesis / Q000502:physiology*; D011971:Receptors, Immunologic / Q000096:biosynthesis / Q000097:blood / Q000172:deficiency / Q000235:genetics / Q000502:physiology*
D015703:Antigens, CD; D006131:Growth Inhibitors; C105299:LILRB1 protein, human; C491341:LILRB2 protein, human; C527699:LILRB3 protein, human; C107907:LILRB4 protein, human; D000075362:Leukocyte Immunoglobulin-like Receptor B1; D008562:Membrane Glycoproteins; C105949:Pirb protein, mouse; D020033:Protein Isoforms; D053245:RANK Ligand; D011956:Receptors, Cell Surface; D011961:Receptors, Fc; D011971:Receptors, Immunologic; C505688:TNFSF11 protein, human; D016173:Macrophage Colony-Stimulating Factor