School of Pharmacy, Fujian Medical University, Fuzhou, Fujian 350122, China.
Department of Radiotherapy, Cancer Center, the First Affiliated Hospital of Fujian Medical University, Fuzhou, Fujian 350004, China; Key Laboratory of Radiation Biology of Fujian Higher Education Institutions, The First Affiliated Hospital of Fujian Medical University, Fuzhou, Fujian 350004, China.
Int Immunopharmacol. 2022 Oct;111:109179. doi: 10.1016/j.intimp.2022.109179. Epub 2022 Aug 24.
Macrophage polarization is modulated by many different stimuli. However, the effect of fibrotic extracellular matrix (ECM) on macrophage polarization remains unclear. In this study, a mouse model of radiation induced pulmonary fibrosis (RIPF) was established. Alveolar macrophages (AMs) were seeded on separated decellularized ECM respectively derived from early RIPF lung tissue (dECM-RIPF) and normal lung tissue (dECM-Nor), on which the polarization of AMs was examined. By way of bio-AFM analysis, a significant difference in surface roughness, but no difference in stiffness, was found between dECM-RIPF and dECM-Nor. Compared with dECM-Nor, dECM-RIPF induced a higher M1 activation and increased the levels of TNF-α, IL-6 and IL-1β, while it showed no significant effect M2 density. Nevertheless, such effects induced by dECM-RIPF could be abrogated by the integrin pan-inhibitor. Furthermore, dECM-RIPF caused integrin-dependent activation of NFκB, and NFκB inhibitor was capable of inhibiting dECM-RIPF-induced AMs proliferation and M1 activation. Animal experiments showed that NFκB inhibitor alleviated RIPF mainly through inhibiting M1 activation and down-regulating the levels of inflammatory cytokines. Our results showed that differential biophysical signaling from the fibrotic ECM of early RIPF promoted AMs polarization towards a M1 phenotype via integrin-NFκB. Inhibition of M1 activation may be an attractive approach for treating RIPF.
巨噬细胞极化受多种不同刺激调节。然而，纤维化细胞外基质（ECM）对巨噬细胞极化的影响尚不清楚。在本研究中，建立了放射性诱导肺纤维化（RIPF）的小鼠模型。分别将肺泡巨噬细胞（AMs）接种在源自早期 RIPF 肺组织（dECM-RIPF）和正常肺组织（dECM-Nor）的分离去细胞 ECM 上，以检查 AMs 的极化情况。通过生物原子力显微镜（AFM）分析，发现 dECM-RIPF 的表面粗糙度有显著差异，但硬度无差异。与 dECM-Nor 相比，dECM-RIPF 诱导更高的 M1 激活，并增加 TNF-α、IL-6 和 IL-1β 的水平，而对 M2 密度无显著影响。然而，dECM-RIPF 引起的这种作用可以被整联蛋白泛抑制剂所阻断。此外，dECM-RIPF 引起整合素依赖性 NFκB 激活，NFκB 抑制剂能够抑制 dECM-RIPF 诱导的 AMs 增殖和 M1 激活。动物实验表明，NFκB 抑制剂主要通过抑制 M1 激活和下调炎症细胞因子水平来缓解 RIPF。我们的结果表明，来自早期 RIPF 的纤维化 ECM 的不同生物物理信号通过整联蛋白-NFκB 促进 AMs 向 M1 表型极化。抑制 M1 激活可能是治疗 RIPF 的一种有吸引力的方法。
