HDAC6 inhibitor accelerates wound healing by inhibiting tubulin mediated IL-1β secretion in diabetic mice
| Autor: | Kalyani Karnam, Sriharshini Goli, Onkar P. Kulkarni, Kavitha Sedmaki, Venkata Vamsi Krishna Venuganti, Ganesh Routholla, Pravesh Sharma, Balaram Ghosh |
|---|---|
| Rok vydání: | 2019 |
| Předmět: |
0301 basic medicine
Lipopolysaccharides Male Indoles Angiogenesis Blotting Western Interleukin-1beta Stimulation Pharmacology Histone Deacetylase 6 Hydroxamic Acids Real-Time Polymerase Chain Reaction 03 medical and health sciences Mice 0302 clinical medicine Downregulation and upregulation medicine Animals Secretion Enzyme Inhibitors Molecular Biology Chemistry Macrophages Nocodazole Inflammasome HDAC6 Immunohistochemistry Endotoxemia Interleukin-10 Mice Inbred C57BL Interleukin 10 030104 developmental biology Glucose RAW 264.7 Cells 030220 oncology & carcinogenesis Molecular Medicine Wound healing medicine.drug |
| Zdroj: | Biochimica et biophysica acta. Molecular basis of disease. 1866(11) |
| ISSN: | 1879-260X |
| Popis: | Delayed wound healing in diabetes is characterized by sustained activation of inflammasome and increased expression of IL-1β in macrophages. Identification and validation of novel pathways to regulate IL-1β 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-β1) in the late phase of healing. Protein analysis of the diabetic wounds treated with TSA showed increased acetylated α-tubulin and decreased levels of mature IL-1β with no significant effect on the expression of pro-IL-1β, pro-caspase-1 and active caspase-1. In in vitro assays, macrophages exhibited upregulation of HDAC6, IL-1β and downregulation of IL-10 upon stimulation with high glucose and LPS. TSA inhibited the IL-1β secretion and promoted IL-10 in stimulated macrophages with high glucose and LPS. Further investigations showed that TSA inhibits IL-1β release by inhibiting tubulin dependent lysosomal exocytosis without affecting its transcription and maturation. Nocodazole (known acetylation inhibitor) pre-treatment inhibited TSA effect on IL-1β 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. |
| Databáze: | OpenAIRE |
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