Department of Cardiovascular Surgery, Zhongnan Hospital of Wuhan University, Wuhan 430071, China; Hubei Provincial Engineering Research Center of Minimally Invasive Cardiovascular Surgery, Wuhan 430071, China; Wuhan Clinical Research Center for Minimally Invasive Treatment of Structural Heart Disease, Wuhan 430071, China.
Department of Cardiovascular Surgery, Zhongnan Hospital of Wuhan University, Wuhan 430071, China; Hubei Provincial Engineering Research Center of Minimally Invasive Cardiovascular Surgery, Wuhan 430071, China; Wuhan Clinical Research Center for Minimally Invasive Treatment of Structural Heart Disease, Wuhan 430071, China.
Int Immunopharmacol. 2023 May;118:110070. doi: 10.1016/j.intimp.2023.110070. Epub 2023 Mar 30.
Rationale Idiopathic pulmonary fibrosis (IPF) is a lung disease with high mortality, limited treatment options and an unknown aetiology. M2 macrophages play a critical role in the pathological process of IPF. Triggering receptor expressed on myeloid cells-2 (TREM2) participates in the regulation of macrophages, although its role in IPF remains elusive.
This study examined the role of TREM2 in macrophage regulation using a well-established bleomycin (BLM)-induced pulmonary fibrosis (PF) mouse model. TREM2 insufficiency was induced by intratracheal treatment with TREM2-specific siRNA. The effects of TREM2 on IPF were evaluated using histological staining and molecular biological methods.
TREM2 expression levels were significantly elevated in the lungs of IPF patients and mice with BLM-induced pulmonary fibrosis mice. Bioinformatics analysis revealed that IPF patients with higher TREM2 expression had a shorter survival time, and that TREM2 expression was closely associated with fibroblasts and M2 macrophages. Gene Ontology (GO) enrichment analysis showed that found TREM2-related differentially expressed genes (DEGs) were associated with inflammatory responses, extracellular matrix (ECM) and collagen formation. Single-cell RNA sequencing analysis revealed that TREM2 was predominantly expressed in macrophages. TREM2 insufficiency inhibited BLM-induced pulmonary fibrosis and M2 macrophage polarization. Mechanistic studies showed that TREM2 insufficiency suppressed the activation of STAT6 and the expression of fibrotic factors such as Fibronectin (Fib), Collagen I (Col I) and α- smooth muscle actin (α-SMA).
Our study showed that TREM2 insufficiency might alleviate pulmonary fibrosis possibly through macrophage polarization regulation via STAT6 activation, providing a promising macrophage-related approach for the clinical therapy of pulmonary fibrosis.
特发性肺纤维化（IPF）是一种死亡率高、治疗选择有限且病因不明的肺部疾病。M2 巨噬细胞在 IPF 的病理过程中发挥关键作用。髓样细胞触发受体 2（TREM2）参与巨噬细胞的调节，尽管其在 IPF 中的作用仍不清楚。
本研究使用已建立的博来霉素（BLM）诱导的肺纤维化（PF）小鼠模型，研究了 TREM2 在巨噬细胞调节中的作用。通过气管内给予 TREM2 特异性 siRNA 诱导 TREM2 缺陷。使用组织学染色和分子生物学方法评估 TREM2 对 IPF 的影响。
IPF 患者和 BLM 诱导的肺纤维化小鼠的肺中 TREM2 表达水平显著升高。生物信息学分析显示，TREM2 表达较高的 IPF 患者生存时间较短，TREM2 表达与成纤维细胞和 M2 巨噬细胞密切相关。基因本体论（GO）富集分析显示，发现的 TREM2 相关差异表达基因（DEGs）与炎症反应、细胞外基质（ECM）和胶原形成有关。单细胞 RNA 测序分析显示，TREM2 主要在巨噬细胞中表达。TREM2 缺陷抑制 BLM 诱导的肺纤维化和 M2 巨噬细胞极化。机制研究表明，TREM2 缺陷抑制 STAT6 的激活和纤连蛋白（Fib）、I 型胶原（Col I）和α-平滑肌肌动蛋白（α-SMA）等纤维化因子的表达。
我们的研究表明，TREM2 缺陷可能通过 STAT6 激活调节巨噬细胞极化来减轻肺纤维化，为肺纤维化的临床治疗提供了一种有前途的巨噬细胞相关方法。
