Diabetes exacerbates destructive inflammation by activating the CD137L-CD137 axis in dendritic and IL-17+ T cells
Xin Huang, Min Liu, Michael V. Gonzalez, Rahul Debnath, Hamideh Afzali, Yongwon Choi, Su Ah Kim, Kang I. Ko, Dana T. Graves
Xin Huang, Min Liu, Michael V. Gonzalez, Rahul Debnath, Hamideh Afzali, Yongwon Choi, Su Ah Kim, Kang I. Ko, Dana T. Graves
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Research Article Immunology Inflammation

Diabetes exacerbates destructive inflammation by activating the CD137L-CD137 axis in dendritic and IL-17+ T cells

Abstract

Periodontal disease, a bacterial infection affecting a large percentage of the world’s population, is an important risk factor for several systemic diseases and is significantly worsened by diabetes. To investigate how diabetes exacerbates the inflammatory response to bacteria in this disease, we combined insights from murine and human studies. Through single-cell RNA-Seq, we identified a compelling hyperglycemia-driven molecular pathway: the upregulation of CD137L in dendritic cells (DCs) and increased expression of its receptor, CD137, in IL-17+ T cells. The CD137L-CD137 axis emerged as a pivotal mediator of diabetes-induced inflammatory tissue destruction. Antibody-mediated inhibition of CD137L markedly reduced diabetes-driven bone loss, neutrophil recruitment, expansion of γδ T cells, and excessive infiltration by IL-17A+ cells. In vitro studies further validated these findings and established that dysregulation of DCs mediated by high glucose levels dramatically altered γδ T cell activity in co-culture systems via CD137L. The essential role of DCs as CD137L producers in vivo was definitively established through lineage-specific Akt1 deletion, which abrogated CD137L expression in DCs and reversed the adverse effects of hyperglycemia on increased IL-17+ T cells and loss of Tregs in vivo. Conversely, activation of CD137 with an agonist in normal animals recapitulated diabetes-induced abnormalities in the inflammatory response and accelerated bone loss. These findings elucidate a key mechanism underlying diabetes-induced immune dysregulation and inflammatory damage, and point to the CD137L-CD137 pathway as a promising therapeutic target, offering potential insights into mitigating other diabetes-associated complications linked to inflammatory changes.

Authors

Xin Huang, Min Liu, Michael V. Gonzalez, Rahul Debnath, Hamideh Afzali, Yongwon Choi, Su Ah Kim, Kang I. Ko, Dana T. Graves

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Figure 9

The CD137L-CD137 axis plays a key role in diabetes-altered inflammation.

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The CD137L-CD137 axis plays a key role in diabetes-altered inflammation....
Diabetic mice received a CD137L antagonist or control Ab, and NG mice received a CD137 agonist or control Ab. Periodontitis was induced as in Figure 1. (A) Representative flow cytometry plots of CD45+ leukocytes from NG+Control Ab, NG+Agonist Ab, Diab+Control Ab, and Diab+Antagonist Ab groups. (B) Quantitation of CD45+ cells per total live cells. (C) Representative flow cytometry plots of Ly6G+CD45+ neutrophils. (D) Quantitation of Ly6G+ neutrophils per total CD45+ cells. (E) Representative flow cytometry plots of γδ T cells pregated as CD45+CD3+Zombie–. (F) Quantitation of γδ T cells per total CD3+ T cells. (G) Representative IL-17A immunofluorescence staining of periodontal tissues, with IL-17A (red) and DAPI (blue) nuclear staining. High-power magnification insets (top row) are identified from lower power images by white boxes. (H) Quantitation of IL-17A+ cells per mm2 of connective tissue area by immunofluorescence. (I) For in vitro studies, γδ T cells were cultured alone or co-cultured with DCs under NG or HG conditions. Proliferation of γδ T cells was assessed by Ki67+γδTCR+ cells. (J) Quantitation of proliferating γδ T cells from DC–γδ T cell co-cultures incubated with a CD137 agonist or CD137L antagonist. Cultures without agonist or antagonist Ab were incubated with control Ab. (K) Flow cytometric analysis of IL-17A+γδ T cells without or with DC co-cultures in NG or HG medium. (L) Quantitation of IL-17A+γδ T cells in γδ T cell and DC co-cultures incubated with CD137 agonist or CD137L antagonist. Cultures without agonist or antagonist Ab were incubated with control Ab. For in vivo analyses (B, D, F, and H), n = 3–7 per group; for in vitro assays (I–L), n = 3 per group. Data are presented as mean ± SEM. Statistical significance was determined by 1-way ANOVA with Tukey’s post hoc test. *P < 0.05.