M2‐Like Macrophages Exhibit Sialic Acid‐Enhanced Efferocytosis via the Siglec CD22

ABSTRACT The sialic acid/Siglec axis is an important immunologic regulatory pathway in which host‐specific α2,6‐sialylated glycans are recognized as markers of self. CD22, known primarily as a surface receptor on B cells, directly prevents autoantigen responses through concurrent recognition of α2,6‐linked sialic acids. Here, we report that CD22 is expressed in macrophages polarized to an M2‐like, immunomodulatory phenotype. Tissue‐resident macrophage populations classically showing an M2‐like skew, such as in the lung, were found to be significantly enriched for CD22 expression. We also discovered that CD22 promotes efferocytosis of sialylated glycoproteins and apoptotic debris and is associated with increased protein processing but reduced T cell activation. These findings support a model whereby CD22 + M2‐like macrophages participate in the resolution of inflammation and a return to tissue homeostasis via the clearance of host‐derived α2,6‐sialylated debris, degrading this material without further exacerbation of T cell‐mediated inflammation.