Recent Publications

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   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. 

   The interactions between environmental glycans and glycan-binding proteins modulate a host of processes across biological systems. The Siglec/sialic acid axis has gained increasing attention as an immunologic checkpoint due to its involvement with reducing inflammatory processes and promoting tumor growth. Siglec-2, or CD22, has been extensively characterized as a co-receptor for the B cell receptor (BCR) and is critical for the prevention of self-reactive B cell responses through its recognition of α2,6-linked sialic acids. More recently, CD22 has emerged as an important receptor for macrophage biology. Here, we investigate the consequences of genetic ablation of CD22 in murine macrophages (CD22KO). Aged CD22KO mice developed a fatty liver phenotype similar to that seen in aged animals lacking hepatocyte α2,6-sialylation (HcKO). CD22KO bone marrow-derived macrophages (BMDMs) exhibited few differences in canonical markers of M1-like and M2-like polarization, but M2-like CD22KO BMDMs showed a pro-inflammatory shift in transcriptome and a reduction in endocytic and efferocytotic capacity. These data suggest that CD22 in murine M2-like macrophages is strongly associated with a homeostatic transcriptional profile and directly participates in immunologically silent housekeeping functions such as clearance of sialylated-self debris through the Siglec-sialic acid axis. 

IgG is a key to adaptive immunity and a critical platform for drug design. Sialic acid on the conserved glycan within the Fc domain is believed to promote anti-inflammatory IgG function; however, regulation of sialylation remains poorly defined. We previously showed that IgG sialylation is primarily mediated by B cell-extrinsic processes in mice. Here, we discovered that IgG sialylation occurs in the subcellular compartments of the FcRn-mediated IgG recycling pathway of endothelial cells. This process is down-regulated by inflammatory signals and up-regulated during gestation, providing mechanistic insight into the epidemiology associating IgG glycosylation, pregnancy and inflammatory disease. These findings demonstrate that plasma-localized IgG glycosylation is dynamically altered by the endothelium, revealing a potential mechanism through which the function of all endogenous and administered IgG and Fc-containing pharmaceuticals could be altered.