Progranulin-dependent repair function of regulatory T cells drives bone-fracture healing
Ruiying Chen, Xiaomeng Zhang, Bin Li, Maurizio S. Tonetti, Yijie Yang, Yuan Li, Beilei Liu, Shujiao Qian, Yingxin Gu, Qingwen Wang, Kairui Mao, Hao Cheng, Hongchang Lai, Junyu Shi
Ruiying Chen, Xiaomeng Zhang, Bin Li, Maurizio S. Tonetti, Yijie Yang, Yuan Li, Beilei Liu, Shujiao Qian, Yingxin Gu, Qingwen Wang, Kairui Mao, Hao Cheng, Hongchang Lai, Junyu Shi
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Research Article Bone biology

Progranulin-dependent repair function of regulatory T cells drives bone-fracture healing

Abstract

Local immunoinflammatory events instruct skeletal stem cells (SSCs) to repair/regenerate bone after injury, but mechanisms are incompletely understood. We hypothesized that specialized Tregs are necessary for bone repair and interact directly with SSCs through organ-specific messages. Both in human patients with bone fracture and a mouse model of bone injury, we identified a bone injury–responding Treg subpopulation with bone-repair capacity marked by CCR8. Local production of CCL1 induced a massive migration of CCR8+ Tregs from periphery to the injury site. Depending on secretion of progranulin (PGRN), a protein encoded by the granulin (Grn) gene, CCR8+ Tregs supported the accumulation and osteogenic differentiation of SSCs and thereby bone repair. Mechanistically, we revealed that CCL1 enhanced expression levels of basic leucine zipper ATF-like transcription factor (BATF) in CCR8+ Tregs, which bound to the Grn promoter and increased Grn translational output and then PGRN secretion. Together, our work provides a new perspective in osteoimmunology and highlights possible ways of manipulating Treg signaling to enhance bone repair and regeneration.

Authors

Ruiying Chen, Xiaomeng Zhang, Bin Li, Maurizio S. Tonetti, Yijie Yang, Yuan Li, Beilei Liu, Shujiao Qian, Yingxin Gu, Qingwen Wang, Kairui Mao, Hao Cheng, Hongchang Lai, Junyu Shi

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Figure 8

BATF modulates PGRN expression in the injury-responding Tregs.

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BATF modulates PGRN expression in the injury-responding Tregs. (A) De no...
(A) De novo motif-enrichment analysis of ATAC-Seq peaks associated with Treg-Cntrl cell–expressed genes encoding transcription factors. Random background regions serve as a control. (B) De novo motif-enrichment analysis of ATAC-Seq peaks associated with Treg-injury cells–expressed genes encoding transcription factors. Random background regions serve as a control. (C) Chromatin accessibility of the Batf locus in SP Tregs and BM Tregs in control and injury group. (D) Violin plot showing the expression level of BATF in Treg1 subset and Treg2 subset. (E) Representative images of the expression of BATF in CCR8+ Tregs and CCR8– Tregs. (F) Quantification of the expression of BATF in CCR8+ Tregs and CCR8– Tregs. n = 3 per group. (G) Chromatin accessibility of the Grn locus in BM Tregs with BATF ChIP-Seq data. (H) Diagram graph showing the binding sites of Grn with Batf. (I) Dual luciferase reporter assay in HEK293A cells cotransduced with luciferase reporter driven by WT or mutant Grn promoter and expression plasmid of Batf. n = 3 per group. (J) Representative images and quantification of BATF+ and PGRN+ CCR8+ Tregs with or without treatment with CCL1 (10 ng/ml or 50 ng/ml). n = 3–4 per group. All data are shown as mean ± SEM. *P ≤ 0.05; **P ≤ 0.01; ***P ≤ 0.005; ****P ≤ 0.001, as determined by 1-way ANOVA with Bonferroni’s multiple-comparisons test.