The HDAC10 instructs macrophage M2 program via deacetylation of STAT3 and promotes allergic airway inflammation

Abstract

Background: Perturbation of macrophage homeostasis is one of the key mechanisms of airway inflammation in asthma. However, the exact mechanisms remain poorly understood. Objectives: We sought to examine the role of histone deacetylase (HDAC) 10 as an epigenetic regulator that governs macrophage M2 program and promotes airway inflammation in asthma, and to elucidate the underlying mechanisms. Methods: Peripheral blood and airway biopsies were obtained from healthy individuals and asthmatic patients. Asthma was induced by exposure to allergen in mice with myeloid-specific deletion of Hdac10 (Hdac10 fl/fl -LysMCre) mice. HDAC10 inhibitor Salvianolic acid B (SAB), STAT3 selective agonist Colivelin, and the specific PI3K/Akt activator 1,3-Dicaffeoylquinic acid (DA) were also used in asthmatic mice. For cell studies, THP1 cells, primary mouse bone marrow derived macrophage (BMDMs) were used and related signaling pathways was investigated. Results: HDAC10 expression was highly expressed by macrophages and promoted M2 macrophage activation and airway inflammation in asthmatic patients and mice. Hdac10 fl/fl -LysMCre mice were protected from airway inflammation in experimental asthma model. Hdac10 deficiency significantly attenuated STAT3 expression and decreased M2 macrophage polarization following allergen exposure. Mechanistically, HDAC10 directly binds STAT3 for deacetylation in macrophages, by which it promotes STAT3 expression and activates the macrophage M2 program. Importantly, we identified SAB as a HDAC10 inhibitor that had protective effects against airway inflammation in mice. Conclusions: Our results revealed that HDAC10-STAT3 interaction governs macrophage polarization to promote airway inflammation in asthma, implicating HDAC10 as a therapeutic target.

Identification of key genes and biological pathways in chronic obstructive pulmonary disease using bioinformatics and next generation sequencing data analysis

“…PHGDH (phosphoglycerate dehydrogenase) [1429], BRCA1 [1497], FOXA1 [1498], CREB1 [1499], ESR1 [1500] and STAT3 [1501] might be a prognostic biomarker and potential therapeutic target for patients with osteoporosis. BRCA1 [1502], ESR1 [1503] and STAT3 [1504] have been linked to the start of airway inflammation. STAT3 [1505] is implicated in polycythemia.…”

Impacts of epigenetic reprogramming on innate immunity

“…Epigenetic modifiers such as histone methyltransferases and acetyltransferases exhibit differential expression in macrophage M1/M2 states, suggesting they play a role in maintaining and regulating macrophage M1/M2 polarization [122] . For instance, HDAC10 is upregulated in macrophages and the upregulation promotes activation of mouse M2 macrophages [123] . Inhibiting HDAC6 and HDAC8 suppresses macrophage M2 polarization [124][125][126] .…”

S100A8/9 modulates perturbation and glycolysis of macrophages in allergic asthma mice

“…Arginase 1 (Arg1), found in the inflammatory zone 1 (Fizz-1) is also a biomarker of M2 macrophages ( Xu et al, 2020 ). In addition, activation of M2 macrophages promotes airway inflammation in asthma ( Zhong et al, 2023 ). The homeostasis of macrophage perturbations is a key mechanism of airway inflammation in asthma; however, the exact mechanism remains poorly understood.…”