Rashid Sarah, Song Dezhi, Yuan Jinbo, Mullin Benjamin H, Xu Jiake
School of Biomedical Sciences, University of Western Australia, Perth, Western Australia, Australia.
Research Centre for Regenerative Medicine, Guangxi Medical University, Nanning, Guangxi, China.
J Cell Physiol. 2022 Mar;237(3):1711-1719. doi: 10.1002/jcp.30654. Epub 2021 Dec 10.
Siglec-15, a Siglec family member and type-1 transmembrane protein, is expressed mainly in human macrophages and dendritic cells. It is comprised of a lysine-containing transmembrane domain, two extracellular immunoglobulin (Ig)-like domains and a short cytoplasmic domain. Siglec-15 is highly conserved in vertebrates and acts as an immunoreceptor. It exerts diverse functions on osteoclast physiology as well as the tumor microenvironment. Siglec-15 interacts with adapter protein DAP12 - Syk signaling pathway to regulate the RANKL/RANK-mediated PI3K, AKT, and ERK signaling pathways during osteoclast formation in vitro. Consistently, the lack of the Siglec-15 gene in mice leads to impaired osteoclast activity and osteopetrosis in vivo. In addition, Siglec-15 is expressed by tumor-associated macrophages (TAMs) and regulates the tumor microenvironment by activating the SYK/MAPK signaling pathway. Interestingly, Siglec-15 shares sequence homology to programmed death-ligand 1 (PD-L1) and has a potential immune-regulatory role in cancer immunology. Thus, Siglec-15 might also represent an alternative target for the treatment of cancers that do not respond to anti-PD-L1/PD-1 immunotherapy. Understanding the role of Siglec-15 in osteoclastogenesis and the tumor microenvironment will help us to develop new treatments for bone disorders and cancer.
唾液酸结合免疫球蛋白样凝集素15（Siglec-15）是唾液酸结合免疫球蛋白样凝集素家族成员和I型跨膜蛋白，主要在人类巨噬细胞和树突状细胞中表达。它由一个含赖氨酸的跨膜结构域、两个细胞外免疫球蛋白（Ig）样结构域和一个短的胞质结构域组成。Siglec-15在脊椎动物中高度保守，作为一种免疫受体发挥作用。它在破骨细胞生理学以及肿瘤微环境中发挥多种功能。在体外破骨细胞形成过程中，Siglec-15与衔接蛋白DAP12 - Syk信号通路相互作用，以调节RANKL/RANK介导的PI3K、AKT和ERK信号通路。同样，小鼠中Siglec-15基因的缺失会导致体内破骨细胞活性受损和骨质石化。此外，肿瘤相关巨噬细胞（TAM）表达Siglec-15，并通过激活SYK/MAPK信号通路调节肿瘤微环境。有趣的是，Siglec-15与程序性死亡配体1（PD-L1）具有序列同源性，在癌症免疫学中具有潜在的免疫调节作用。因此，Siglec-15也可能代表一种治疗对抗PD-L1/PD-1免疫疗法无反应的癌症的替代靶点。了解Siglec-15在破骨细胞生成和肿瘤微环境中的作用将有助于我们开发针对骨疾病和癌症的新疗法。
