HDAC6 inhibitor accelerates wound healing by inhibiting tubulin mediated IL-1β secretion in diabetic mice

BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR BASIS OF DISEASE

卷:1866

Article

Karnam, Kalyani¹  Sedmaki, Kavitha¹  Sharma, Pravesh¹  Routholla, Ganesh¹  Goli, Sriharshini¹  Ghosh, Balaram¹  Venuganti, Venkata Vamsi Krishna¹  Kulkarni, Onkar Prakash¹ 

[1] Birla Inst Technol & Sci Pilani, Dept Pharm, Hyderabad Campus, Hyderabad, India

关键词: HDAC6;    Diabetic wounds;    IL-1 beta;    IL-10;    Macrophages;   

DOI  :  10.1016/j.bbadis.2020.165903

来源: Elsevier

【 摘 要 】

Delayed wound healing in diabetes is characterized by sustained activation of inflammasome and increased expression of IL-1 beta in macrophages. Identification and validation of novel pathways to regulate IL-1 beta expression will provide therapeutic targets for diabetic wounds. Here we report sustained over-expression of histone deacetylase 6 (HDAC6) in wounds of diabetic mice and its role in delayed wound healing. Topical application of HDAC6 inhibitor; Tubastatin A (TSA) gel promoted the wound healing in diabetic mice. TSA hydrogel reduced the infiltration of neutrophils, T-cells and macrophages in the early phase of wound healing. TSA treatment promoted the wound healing by inducing collagen deposition, angiogenesis (CD31) and fibrotic factors (TGF-beta 1) in the late phase of healing. Protein analysis of the diabetic wounds treated with TSA showed increased acetylated alpha-tubulin and decreased levels of mature IL-1 beta with no significant effect on the expression of pro-IL-1 beta, pro-caspase-1 and active caspase-1. In in vitro assays, macrophages exhibited upregulation of HDAC6, IL-1 beta and downregulation of IL-10 upon stimulation with high glucose and LPS. TSA inhibited the IL-1 beta secretion and promoted IL-10 in stimulated macrophages with high glucose and LPS. Further investigations showed that TSA inhibits IL-1 beta release by inhibiting tubulin dependent lysosomal exocytosis without affecting its transcription and maturation. Nocodazole (known acetylation inhibitor) pre-treatment inhibited TSA effect on IL-1 beta secretion in high glucose stimulated macrophages. Overall, our findings indicate that sustained HDAC6 expression in diabetic wounds contributes to impaired healing responses and HDAC6 may represent a new therapeutic target for diabetic wounds.

【 授权许可】

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