Disruption of hepatocyte Sialylation drives a T cell-dependent pro-inflammatory immune tone

• Published in: Glycoconjugate journal Vol. 37; no. 3; pp. 395 - 407
• Main Authors: Oswald, Douglas M., Zhou, Julie Y., Jones, Mark B., Cobb, Brian A.
• Format: Journal Article
• Language: English
• Published: New York Springer US 01.06.2020; Springer Nature B.V
• Subjects: Acids; Anergy; Asthma; Biochemistry; Biomedical and Life Sciences; Catalysis; CD22 antigen; Cell interactions; Effector cells; Experimental allergic encephalomyelitis; Fatty liver; Homeostasis; Immunological memory; Inflammation; Life Sciences; Liver; Liver diseases; Lymphocytes; Lymphocytes T; Macrophages; Memory cells; Morbidity; Myelin; Oligodendrocyte-myelin glycoprotein; Original Article; Pathology; Polysaccharides; Sialic acids; Spleen; ST6Gal1; Sialic acid; Glycobiology; Liver; T cell; EAE; IgG; Inflammation; Sialylation; Asthma; Macrophage
• ISSN: 0282-0080; 1573-4986; 1573-4986
• DOI: 10.1007/s10719-020-09918-y

Through the catalysis of α2,6-linked sialylation, the enzyme ST6Gal1 is thought to play key roles in immune cell communication and homeostasis. Of particular importance, glycans with terminal α2,6-sialic acids are known to negatively regulate B cell receptor signaling and are associated with an immunosuppressive tumor microenvironment that promotes T cell anergy, suggesting that α2,6-sialic acids are a key immune inhibitory signal. Consistent with this model, mice harboring a hepatocyte-specific ablation of ST6Gal1 (H-cKO) develop a progressive and severe non-alcoholic fatty liver disease characterized by steatohepatitis. Using this H-cKO mouse, we have further discovered that loss of hepatocyte α2,6-sialylation not only increases the inflammatory state of the local tissue microenvironment, but also systemic T cell-dependent immune responses. H-cKO mice responded normally to innate and passively induced inflammation, but showed significantly increased morbidity in T cell-dependent house dust mite-antigen (HDM)-induced asthma and myelin oligodendrocyte glycoprotein (MOG) peptide-induced experimental autoimmune encephalomyelitis (EAE). We further discovered that H-cKO mice have a profound shift toward effector/memory T cells even among unchallenged mice, and that macrophages from both the liver and spleen expressed the inhibitory and α2,6-sialic acid-specific glycan binding molecule CD22. These findings align with previously reported pro-inflammatory changes in liver macrophages, and support a model in which the liver microenvironment sets a systemic immune tone that is regulated by tissue α2,6-sialylation and mediated by liver macrophages and systemic T cells.