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

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Abstract

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.

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Abbreviations

WBC:

white blood cell

ThioG:

thioglycollate

HDM:

house dust mite

CAIA:

collagen antibody induced arthritis

EAE:

experimental autoimmune encephalomyelitis

MOG:

myelin oligodendrocyte glycoprotein

CFA:

complete Freund’s adjuvant

PTX:

pertussis toxin

LPS:

lipopolysaccharide

PBS:

phosphate buffered saline

ST6Gal1:

β-galactoside α-2,6-sialyltransferase

H-cKO:

hepatocyte conditional knockout of ST6Gal1

Siglec:

sialic acid binding immunoglobulin-type lectin

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Acknowledgements

We would like to Carlos Alvarez for valuable scientific discussions and feedback, Jill M. Cavanaugh for technical assistance in the maintenance of the mouse colony, and Lori S.C. Kreisman for general laboratory support. Moreover, we thank Alex Huang, MD, PhD for equipment for histological imaging, and the Cytometry & Microscopy Shared Resource of the Case Comprehensive Cancer Center for equipment and assistance with flow cytometry-based experiments. This work was made possible by grants from The National Institutes of Health (R01-GM115234) to BAC, the National Institutes of Health (T32-AI089474) to DMO and JYZ, and the National Institutes of Health (P30CA043703) to the Case CCC.

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  1. Department of Pathology, School of Medicine, Case Western Reserve University, 10900 Euclid Avenue, Cleveland, OH, 44160, USA

    Douglas M. Oswald, Julie Y. Zhou, Mark B. Jones & Brian A. Cobb

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  1. Douglas M. Oswald
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  2. Julie Y. Zhou
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DMO, experimental design, data collection and analysis, manuscript writing, funding; JYZ, experimental design, data collection and analysis; MBJ, experimental design; BAC, experimental design, data analysis, manuscript writing, funding.

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Correspondence to Brian A. Cobb.

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Oswald, D.M., Zhou, J.Y., Jones, M.B. et al. Disruption of hepatocyte Sialylation drives a T cell-dependent pro-inflammatory immune tone. Glycoconj J 37, 395–407 (2020). https://doi.org/10.1007/s10719-020-09918-y

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