Dual assemblies of an activating immune receptor, MAIR-II, with ITAM-bearing adapters DAP12 and FcRγ chain on peritoneal macrophages

Certain activating immune receptors expressed on myeloid cells noncovalently associate with either DAP12 or Fc epsilon RI gamma (FcR gamma chain), the ITAM-bearing transmembrane adapter proteins. An activating receptor, myeloid-associated Ig-like receptor (MAIR) II, is expressed on a subset of B cells and macrophages in the spleen and peritoneal cavity of mice and associates with DAP12 in these cells. However, we demonstrate here that cross-linking MAIR-II with mAb induced secretion of a significant amount of the inflammatory cytokines TNF-alpha and IL-6 from DAP12(-/-) as well as wild-type (WT) peritoneal macrophages. We show that MAIR-II associates with not only DAP12 but also FcR gamma chain homodimers in peritoneal macrophages. LPS enhanced the FcR gamma chain expression and FcR gamma chain-dependent cell surface expression of MAIR-II and had additive effects on MAIR-II-mediated inflammatory cytokine secretion from peritoneal macrophages. The lysine residue in the transmembrane region of MAIR-II was involved in the association with FcR-y chain as well as DAP12. Our findings present the first case of an activating receptor that uses either DAP12 or FcRC gamma chain as a signaling adapter. The FcR-y chain may provide cooperation with and/or compensation for DAP12 in MAIR-II-mediated inflammatory responses by peritoneal macrophages.