Plexin-A1 and its interaction with DAP12 in immune responses and bone homeostasis

Abstract

Semaphorins and their receptors have diverse functions in axon guidance, organogenesis, vascularization and/or angiogenesis, oncogenesis and regulation of immune responses. The primary receptors for semaphorins are members of the plexin family. In particular, plexin-A1, together with ligand-binding neuropilins, transduces repulsive axon guidance signals for soluble class III semaphorins, whereas plexin-A1 has multiple functions in chick cardiogenesis as a receptor for the transmembrane semaphorin, Sema6D, independent of neuropilins. Additionally, plexin-A1 has been implicated in dendritic cell function in the immune system. However, the role of plexin-A1 in vivo, and the mechanisms underlying its pleiotropic functions, remain unclear. Here, we generated plexin-A1-deficient (plexin-A1(-/-)) mice and identified its important roles, not only in immune responses, but also in bone homeostasis. Furthermore, we show that plexin-A1 associates with the triggering receptor expressed on myeloid cells-2 (Trem-2), linking semaphorin-signalling to the immuno-receptor tyrosine-based activation motif (ITAM)-bearing adaptor protein, DAP12. These findings reveal an unexpected role for plexin-A1 and present a novel signalling mechanism for exerting the pleiotropic functions of semaphorins.

Regulation of immune cell responses by semaphorins and their receptors

“…42 On the other hand, plexin-A1 forms a receptor complex with triggering receptor expressed on myeloid cell (TREM)-2/DNAX-activating protein 12 (DAP12) in osteoclastogenesis. 20 Furthermore, plexin-B1 has been shown to associate with the receptor tyrosine kinases Met and ErbB2, triggering invasive growth of epithelial cells. 19,43 INVOLVEMENT OF 'IMMUNE SEMAPHORINS' IN CELL-CELL INTERACTIONS Sema4D: a semaphorin involved in B-cell/dendritic cell activation Sema4D, also known as CD100, is the first semaphorin protein that was determined to have immunoregulatory functions.…”

“…42,57 In the immune system, plexin-A1 is specifically expressed in DCs, where it mediates the activation of T cells and the production of type I interferon. 20,58,59 The generation of antigen-specific T cells is impaired in plexin-A1 2/2 mice. 20 Sema6D, which is expressed in T cells, B cell and natural killer cells, was identified as a putative ligand for plexin-A1.…”

“…20,58,59 The generation of antigen-specific T cells is impaired in plexin-A1 2/2 mice. 20 Sema6D, which is expressed in T cells, B cell and natural killer cells, was identified as a putative ligand for plexin-A1. 20 Indeed, recombinant Sema6D protein binds to and activates DCs and increases type I interferon production.…”

“…20 Sema6D, which is expressed in T cells, B cell and natural killer cells, was identified as a putative ligand for plexin-A1. 20 Indeed, recombinant Sema6D protein binds to and activates DCs and increases type I interferon production. Plexin-A1 forms a receptor complex with the TREM family of proteins and the adaptor molecule DAP12.…”

“…They were initially identified as repulsive axon guidance molecules that were required to direct neuronal axons to their appropriate targets. 9 More than 20 types of semaphorins have been identified, 10 and they have diverse functions in many physiological process, 11 including cardiogenesis, 12,13 angiogenesis, 14,15 vasculogenesis, 16 tumor metastasis, [17][18][19] osteoclastogenesis 20 and immune regulation. 21,22 In this review, we focus on two functional aspects of semaphorins, their roles in immune cell-cell interactions and immune cell trafficking.…”