A pathogenic role for IL-10 signalling in capillary stalling and cognitive impairment in type 1 diabetes

  • Nat Metab. 2024 Nov;6(11):2082-2099. doi: 10.1038/s42255-024-01159-9.
Sorabh Sharma  1 ,  Manjinder Cheema  1 ,  Patrick L Reeson  1 ,  Kamal Narayana  1 ,  Roobina Boghozian  1 ,  Ana Paula Cota  1 ,  Tara P Brosschot  2 ,  Rachael D FitzPatrick  2 ,  Jakob Körbelin  3 ,  Lisa A Reynolds  2 ,  Craig E Brown  4  5
Affiliations
  • 1. Division of Medical Sciences, University of Victoria, Victoria, British Columbia, Canada.
  • 2. Department of Biochemistry and Microbiology, University of Victoria, Victoria, British Columbia, Canada.
  • 3. Department of Oncology, Hematology and Bone Marrow Transplantation, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
  • 4. Division of Medical Sciences, University of Victoria, Victoria, British Columbia, Canada. [email protected].
  • 5. Department of Psychiatry, University of British Columbia, Vancouver, British Columbia, Canada. [email protected].
PMID: 39496927 DOI: 10.1038/s42255-024-01159-9
Abstract

Vascular pathology is associated with cognitive impairment in diseases such as type 1 diabetes; however, how capillary flow is affected and the underlying mechanisms remain elusive. Here we show that capillaries in the diabetic mouse brain in both sexes are prone to stalling, with blocks consisting primarily of erythrocytes in branches off ascending venules. Screening for circulating inflammatory cytokines revealed persistently high levels of interleukin-10 (IL-10) in diabetic mice. Contrary to expectation, stimulating IL-10 signalling increased capillary obstruction, whereas inhibiting IL-10 receptors with neutralizing antibodies or endothelial specific knockdown in diabetic mice reversed these impairments. Chronic treatment of diabetic mice with IL-10 Receptor neutralizing antibodies improved cerebral blood flow, increased capillary flux and diameter, downregulated haemostasis and cell adhesion-related gene expression, and reversed cognitive deficits. These data suggest that IL-10 signalling has an unexpected pathogenic role in cerebral microcirculatory defects and cognitive impairment associated with Type 1 Diabetes.

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