Emerging roles and therapeutic implications of HDAC2 and IL-17A in steroid-resistant asthma

Abstract

Steroid resistance represents a major clinical problem in the treatment of severe asthma, and therefore a better understanding of its pathogenesis is warranted. Recent studies indicated that histone deacetylase 2 (HDAC2) and interleukin 17A (IL-17A) play important roles in severe asthma. HDAC2 activity is reduced in patients with severe asthma and smoking-induced asthma, perhaps accounting for the amplified expression of inflammatory genes, which is associated with increased acetylation of glucocorticoid receptors. Neutrophilic inflammation contributes to severe asthma and may be related to T helper (Th) 17 rather than Th2 cytokines. IL-17A levels are elevated in severe asthma and correlate with the presence of neutrophils. Restoring the activity of HDAC2 or targeting the Th17 signaling pathway is a potential therapeutic approach to reverse steroid insensitivity.

Keywords: Histone deacetylase 2 (HDAC2); Interleukin 17A (IL-17A); Neutrophilic inflammation; Severe asthma.

Fig. 1

Proposed mechanism of steroid resistance in severe asthma. Th17 cells differentiate when naïve T cells are triggered by cigarette smoke or repeated antigen exposure. Th17-related cytokines (e.g., IL-17A, IL-22) and oxidative stress impair the activity of HDAC2 and increase neutrophil recruitment. This amplifies the inflammatory response to NF-κB activation, but also reduces the anti-inflammatory effect of corticosteroids. APC: antigen-presenting cell; Eos: eosinophil; HDAC2: histone deacetylase 2; IL: Interleukin; MCP-1: monocyte chemoattractant protein-1; MIP-2: macrophage inflammatory protein 2; NF-κB: Nuclear factor-κB; Th2: T helper 2; Th17: T helper 17; TSLP: thymic stromal lymphopoietin.

Fig. 2

Schematic diagram on the role of the interplay between HDAC2 and IL-17A in HDM-induced allergic inflammation. When naïve T cells are triggered by TGF-β, IL-6, IL-1β, IL-21, and IL-23 under HDM stimulation, Th17 cells differentiate and IL-17A expression is subsequently initiated. Among these, the differentiation of Th17 cells secreting IL-17A requires expression of the transcription factors RORγt and STAT3. HDM exposure significantly reduces HDAC2 expression in HBE cells and co-stimulation with IL-17A further reduces HDAC2 activity in the bronchial epithelial cell line. When HDAC2 is reduced, the expression of RORγT increases, and the binding of RORγT to the IL-17A promoter is facilitated, which further reduces HDAC2 expression, thus creating a vicious cycle that ultimately leads to a diminished protective function of HDAC2 in airway inflammation as well as increased neutrophil recruitment, amplifying the inflammatory response to NF-κB activation and causing neutrophilic asthma. GM-CSF: granulocyte-macrophage colony-stimulating factor; HDAC2: histone deacetylase 2; HDM: house dust mite; HBE cell: human bronchial epithelium cell; IL: Interleukin; NF-κB: nuclear factor κB; TGF-β: transforming growth factor-β; RORγT: retinoid-related orphan nuclear receptor γt; STAT3: signal transducer and activator of transcription 3; Th17: T helper 17.