Soluble CD93 is an apoptotic cell opsonin recognized by αxβ2

Efferocytosis is essential for homeostasis and prevention of the inflammatory and autoimmune diseases resulting from apoptotic cell lysis. CD93 is a transmembrane glycoprotein previously implicated in efferocytosis, with mutations in CD93 predisposing patients to efferocytosis‐associated diseases. CD93 is a cell surface protein which is proteolytically shed under inflammatory conditions, but it is unknown how CD93 mediates efferocytosis or whether its efferocytic activity is mediated by the soluble or membrane‐bound form. Herein, using cell lines and human monocytes and macrophages, we demonstrate that soluble CD93 potently opsonizes apoptotic cells but not a broad range of microorganisms, whereas membrane bound CD93 has no phagocytic, efferocytic, or tethering activity. Using mass spectrometry, we identified α_xβ₂ as the receptor which recognizes soluble CD93, and via deletion mutagenesis determined that soluble CD93 binds to apoptotic cells via its C‐Type Lectin‐Like domain and to α_xβ₂ by its EGF‐like repeats. The bridging of apoptotic cells to α_xβ₂ markedly enhanced efferocytosis by macrophages and was abrogated by α_xβ₂ knockdown. Combined, these data elucidate the mechanism by which CD93 regulates efferocytosis and identify a previously unreported opsonin‐receptor system utilized by phagocytes for the efferocytic clearance of apoptotic cells.

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