Myeloid DAP12-associating lectin (MDL)-1 regulates synovial inflammation and bone erosion associated with autoimmune arthritis

Abstract

DNAX adaptor protein 12 (DAP12) is a trans-membrane adaptor molecule that transduces activating signals in NK and myeloid cells. Absence of functional Dap12 results in osteoclast defects and bone abnormalities. Because DAP12 has no extracelluar binding domains, it must pair with cell surface receptors for signal transduction. There are at least 15 known DAP12-associating cell surface receptors with distinct temporal and cell type–specific expression patterns. Our aim was to determine which receptors may be important in DAP12-associated bone pathologies. Here, we identify myeloid DAP12-associating lectin (MDL)-1 receptor (also known as CLEC5A) as a key regulator of synovial injury and bone erosion during autoimmune joint inflammation. Activation of MDL-1 leads to enhanced recruitment of inflammatory macrophages and neutrophils to the joint and promotes bone erosion. Functional blockade of MDL-1 receptor via Mdl1 deletion or treatment with MDL-1-Ig fusion protein reduces the clinical signs of autoimmune joint inflammation. These findings suggest that MDL-1 receptor may be a therapeutic target for treatment of immune-mediated skeletal disorders.

RN486, a Selective Bruton's Tyrosine Kinase Inhibitor, Abrogates Immune Hypersensitivity Responses and Arthritis in Rodents

“…It is not clear whether BCR or FcR is involved because B cell and humoral autoimmunity have not been shown to contribute to AIA. Other possible receptors include CSF1R and myeloid DAP12-associating lectin-1, both of which depend on ITAM-containing DAP12 for signaling, and are implicated in immune arthritis in rodents (Huang et al, 2009;Joyce-Shaikh et al, 2010). Although the exact mechanism remains to be defined, our data suggest that Btk inhibitors may also produce efficacy in autoimmune conditions in which T cell and innate immune responses dominate.…”

“…DAP12 functions as an adaptor protein for multiple receptors, including macrophage colony-stimulating factor 1 receptor (CSF1R) and myeloid DAP12-associating lectin-1 receptor. Both receptors have been implicated in the development of immune arthritis (Huang et al, 2009;Joyce-Shaikh et al, 2010). Also importantly, CSF1R, along with FcR gamma chain, provides a secondary, but indispensable, signal for RANKL to promote osteoclast differentiation and, subsequently, bone resorption (Koga et al, 2004).…”

Inflammatory arthritis increases mouse osteoclast precursors with myeloid suppressor function

“…We were interested to see whether these receptors are present on OCPs and found that receptors providing cosignaling through DAP12 and FcRγ were present on the OCP cell surface. Triggering receptor expressed on monocytes (TREM-2) and myeloid DAP12-associating lectin (MDL-1, also known as CLEC-5A), both DAP12-associated receptors, have been shown to costimulate osteoclast differentiation (27)(28)(29), and MDL-1 was recently implicated in osteoclast differentiation and inflammatory bone loss (30). TREM-2 levels on OCPs were quite low, while MDL-1 expression was high on OCPs ( Figure 4D).…”

A Paradoxical Role for Myeloid-Derived Suppressor Cells in Sepsis and Trauma

“…These samples were originally analyzed for CD4 + and dendritic cell apoptosis (52). The samples were then restained with a novel antibody that is expressed on activated myeloid cells: myeloid DAP12-associating lectin-1 (MDL-1), a cell-surface receptor which has been shown to regulate myeloid cell-associated inflammatory responses (53,54 from bone marrow and the peripheral blood (54). As shown in Figure 6, the pattern of MDL1 expression on human spleens increased dramatically with trauma and sepsis.…”