Cutting Edge: ST8Sia6-Generated α-2,8-Disialic Acids Mitigate Hyperglycemia in Multiple Low-Dose Streptozotocin-Induced Diabetes

J Immunol. 2020 Jun 15;204(12):3071-3076. doi: 10.4049/jimmunol.2000023. Epub 2020 Apr 29.

Abstract

The immune system contains a series of checks and balances that maintain tolerance and prevent autoimmunity. Sialic acid-binding Ig-type lectins (Siglecs) are cell surface receptors found on immune cells and inhibit inflammation by recruiting protein tyrosine phosphatases to ITIMs. Islet-resident macrophages express Siglec-E, and Siglec-E expression decreases on islet-resident macrophages as insulitis progresses in the NOD mouse. The sialyltransferase ST8Sia6 generates α-2,8-disialic acids that are ligands for Siglec-E in vivo. We hypothesized that engaging Siglec-E through ST8Sia6-generated ligands may inhibit the development of immune-mediated diabetes. Constitutive overexpression of ST8Sia6 in pancreatic β cells mitigated hyperglycemia in the multiple low-dose streptozotocin model of diabetes, demonstrating that engagement of this immune receptor facilitates tolerance in the setting of inflammation and autoimmune disease.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antigens, Differentiation, B-Lymphocyte / immunology
  • Antigens, Differentiation, B-Lymphocyte / metabolism
  • Autoimmunity / immunology
  • Diabetes Mellitus / chemically induced*
  • Diabetes Mellitus / immunology
  • Diabetes Mellitus / metabolism*
  • Diabetes Mellitus, Experimental / chemically induced
  • Diabetes Mellitus, Experimental / immunology
  • Diabetes Mellitus, Experimental / metabolism
  • Disease Models, Animal
  • Female
  • Humans
  • Hyperglycemia / immunology
  • Hyperglycemia / metabolism
  • Immune Tolerance / immunology
  • Inflammation / immunology
  • Inflammation / metabolism
  • Insulin-Secreting Cells / immunology
  • Insulin-Secreting Cells / metabolism
  • Ligands
  • Macrophages / metabolism
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Inbred NOD
  • Receptors, Immunologic / immunology
  • Receptors, Immunologic / metabolism
  • Sialic Acid Binding Ig-like Lectin 2 / immunology
  • Sialic Acid Binding Ig-like Lectin 2 / metabolism
  • Sialyltransferases / immunology
  • Sialyltransferases / metabolism*
  • Streptozocin / pharmacology*

Substances

  • Antigens, Differentiation, B-Lymphocyte
  • Ligands
  • Receptors, Immunologic
  • Sialic Acid Binding Ig-like Lectin 2
  • Streptozocin
  • Sialyltransferases