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 8

The CD137L-CD137 axis plays a key role in periodontitis severity in hyperglycemic humans and mice.

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The CD137L-CD137 axis plays a key role in periodontitis severity in hype...
(A and B) Human gingival specimens were obtained from NG (Normogly) individuals and individuals with hyperglycemia (Hypergly), and cells were isolated for flow cytometry. (A) Representative flow cytometry dot plots of CD137L+ and CD11c+ cells from human gingival specimens (n = 4). Cells were pregated for live mononuclear phagocytes (Zombie–CD45+HLA-DR+). (B) Quantitation of CD137L+CD11c+ DCs per total HLA-DR+ mononuclear phagocytes (left) and CD45+ leukocytes per total live cells (Zombie–) in human gingival specimens. (C and D) Diabetic mice were injected with a CD137L-antagonist Ab or control Ab, and NG mice were injected with a CD137-agonist Ab or control Ab. Periodontitis was induced as described in Figure 1. (C) Representative microCT images of 3D reconstruction of the molar teeth. (D) microCT analysis of bone loss was assessed by measuring the distance from the CEJ to the alveolar crest (left) and ratio of the bone area remaining per total area; n = 6–8 biological replicates per group. *P < 0.05, 1-way ANOVA with Tukey’s post hoc test.