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Essential Role of DAP12 Signaling in Macrophage Programming into a Fusion-Competent State

Signaling through the DAP12 adaptor triggers a gene expression profile that makes macrophages competent to fuse and form multinucleated giant cells. Setting the Stage for Fusion DAP12 is an immunotyrosine-based activation motif (ITAM)–containing adaptor protein that interacts with various surface receptors to initiate downstream signaling processes. In the absence of functional DAP12, macrophages fail to fuse to form multinucleated giant cells, an enigmatic immune response involved in granulomatous conditions and the foreign body reaction. In vitro studies showed that DAP12, its associated receptor TREM-2, and the downstream protein tyrosine kinase Syk were all important for maximal fusion capacity of macrophages. In vivo, loss of DAP12 function resulted in the formation of fewer giant cells in response to implantation of a foreign body. Unexpectedly, loss of DAP12 appeared to alter the gene expression profile of the macrophages, rendering them less fusion competent, without compromising their apparent differentiation. Multinucleated giant cells, formed by fusion of macrophages, are a hallmark of granulomatous inflammation. With a genetic approach, we show that signaling through the adaptor protein DAP12 (DNAX activating protein of 12 kD), its associated receptor triggering receptor expressed by myeloid cells 2 (TREM-2), and the downstream protein tyrosine kinase Syk is required for the cytokine-induced formation of giant cells and that overexpression of DAP12 potentiates macrophage fusion. We also present evidence that DAP12 is a general macrophage fusion regulator and is involved in modulating the expression of several macrophage-associated genes, including those encoding known mediators of macrophage fusion, such as DC-STAMP and Cadherin 1. Thus, DAP12 is involved in programming of macrophages through the regulation of gene and protein expression to induce a fusion-competent state.