Depletion of dendritic cells ameliorates proinflammatory state in adipose tissue and endothelial‐dependent vasorelaxation in type 2 diabetes
Authors: Qiu Tianyi , Li Min , Korthuis Ronald J. , Hill Michael A. 
Published: November 2023

Type 2 diabetes (T2DM) causes increased production of proinflammatory cytokines in adipose tissue with such cytokines emanating from resident immune cells, including dendritic cells. A consequence of this local inflammatory environment is impaired vasomotor function of nearby small arteries. We hypothesized that depletion of dendritic cells would decrease proinflammatory cytokine levels and improve endothelial‐dependent vasorelaxation in a mouse model of T2DM. DbHETFlt3l−⁄− and dbFlt3l−/dbFlt3l− mice were generated by cross‐breeding between DbHET and Flt3l−⁄− mice. DbHET, db/db, DbHETFlt3l−⁄− and dbFlt3l−/dbFlt3l− mice were then studied at age 18–22 weeks. VAT (visceral adipose tissue) was collected from DbHET, db/db, DbHETFlt3l−⁄− and dbFlt3l−/dbFlt3l− mice. Single cell suspensions of the stromal vascular fraction were extracted from VAT and, using flow cytometry, dendritic cell numbers detected as CD11c+F4/80− and CD83+CD86+ cell populations. M1 macrophages were detected as the CD11c+F4/80+ cells. VAT and MAT (mesenteric adipose tissue) were collected from DbHET, db/db, DbHETFlt3l−⁄− and dbFlt3l−/dbFlt3l− mice for measurement of mRNA levels for pro‐inflammatory factors TNF‐α and IL‐6 and anti‐inflammatory mediators adiponectin and IL‐10. qPCR analysis was normalized to glyceraldehyde 3‐phosphate dehydrogenase (GAPDH). First order mesenteric arteries (MA) from DbHET, db/db, DbHETFlt3l−⁄− and dbFlt3l−/dbFlt3l− mice were mounted in a wire myograph. 0.5 gram of MAT from each mouse was incubated with its MA for 1 hr while MA incubated without MAT were used as control. Acetylcholine (ACh)‐induced vasorelaxation and phenylephrine (PE)‐induced vasoconstrictor responses were assessed. Increased numbers of dendritic cells and M1 macrophages were evident in adipose tissue of db/db mice. Depletion of Flt3l significantly decreased dendritic cells but not M1 macrophages. TNF‐α and IL‐6 mRNA levels were higher in VAT and MAT of db/db mice compared to DbHET controls. In contrast, these levels were significantly lower in dbFlt3l−⁄−/ dbFlt3l−⁄− compared to db/db mice. Adiponectin mRNA levels were lower in VAT and MAT from db/db mice compared to the DbHET, whereas levels were comparable between dbFlt3l−⁄−/ dbFlt3l−⁄− and db/db mice. IL‐10 mRNA levels were higher in VAT and MAT of db/db mice than DbHET, whereas levels were lower in MAT of dbFlt3l−⁄−/ dbFlt3l−⁄− compared to db/db mice. In DbHET control mice, MAT incubation with arterial segments enhanced ACh‐induced vasorelaxation and reduced PE‐induced vasoconstriction demonstrating an anti‐contractile function of adipose tissue. The enhanced relaxation and anti‐contractile effect of MAT were lost in T2DM mice. Depletion of dendritic cell populations in T2DM mice restored MAT‐induced enhancement of ACh‐induced relaxation, while not restoring the anti‐contractile function of adipose tissue. In conclusion, T2DM is associated with a pro‐inflammatory adipose tissue environment that contributes to vascular dysfunction. Dendritic cell depletion significantly reduces the pro‐inflammatory environment and partially restores vascular function.

Support or Funding Information

NIH HL085119 (MAH) and AA22108 (RJK)