Molecular Features and Stages of Pulmonary Fibrosis Driven by Type 2 Inflammation.
Molecular Features and Stages of Pulmonary Fibrosis Driven by Type 2 Inflammation.
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2 型炎症驱动的肺纤维化的分子特征和阶段。
DOI：
10.1165/rcmb.2022-0301oc
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发表时间：
2023
影响因子：
6.4
通讯作者：
ArunV Subramaniam
中科院分区：
文献类型：
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作者：
H. Mattoo;D. Bangari;Sheila Cummings;Zachary T Humulock;D. Habiel;Ethan Y. Xu;Nathan Pate;R. Resnick;Virginia Savova;G. Qian;Christian Beil;Ercole Rao;F. Nestle;P. Bryce;ArunV Subramaniam
系统性硬化症（SSc）是一种进行性多器官疾病，治疗选择有限。虽然最近使用Romilkimab或SAR 156597（一种双特异性IL-4/IL-13抗体）的概念验证研究表明这些细胞因子在SSc的病理生理学中具有直接作用，但它们对炎症和纤维化之间平衡的贡献尚不清楚。在这里，我们使用Fos相关抗原2过表达转基因小鼠（FRA 2-Tg）确定2型炎症在纤维化发生中的作用，该小鼠发生自发性、年龄依赖性进行性肺纤维化。我们在疾病进展的三个关键阶段定义了炎症和纤维化的分子特征，对应于发病前、炎症主导和纤维化主导生物学，并揭示了在Th 2和M2-巨噬细胞驱动的2型应答增强之后，丝氨酸-细胞因子受体相互作用和抗原加工和呈递途径的早期增加。这种2型炎症在14-18周龄时进展为广泛的纤维化病理，这些基因特征与在患有SSc伴间质性肺病（ILD）的患者的肺中观察到的基因特征显著重叠。这些变化在组织病理学中也很明显，显示血管周围和细支气管周围炎症伴显著嗜酸性粒细胞增多和促纤维化M2样巨噬细胞蓄积，随后快速进展为纤维化伴肺泡壁增厚伴多灶性纤维化带和肺炎体征。重要的是，在炎症阶段用靶向IL-4和IL-13的双特异性抗体治疗消除了Th 2和M2-应答，并导致肺纤维化几乎完全消除。这些数据概括了SSc-ILD患者肺部纤维化进展的重要特征，并增强了我们对SSc进行性病理生物学的理解。本研究还进一步确立了FRA 2-Tg小鼠作为检测SSc-ILD未来治疗药物的有价值工具。
Systemic sclerosis (SSc) is a progressive, multi-organ disease with limited treatment options. While a recent proof-of-concept study using Romilkimab or SAR156597, a bi-specific IL-4/IL-13 antibody, suggests a direct role of these cytokines in the pathophysiology of SSc, their contributions to the balance between inflammation and fibrosis are unclear. Here, we determine the roles of type 2 inflammation in fibrogenesis using a Fos-related antigen 2 overexpressing transgenic mice (FRA2-Tg), which develop a spontaneous, age-dependent progressive lung fibrosis. We defined the molecular signatures of inflammation and fibrosis at three key stages in disease-progression, corresponding to pre-onset, inflammatory dominant, and fibrosis dominant biology, and revealed an early increase in cytokine-cytokine receptor interactions and antigen-processing and presentation pathways followed by enhanced Th2 and M2- macrophage driven type 2 responses. This type-2 inflammation progressed to extensive fibrotic pathology by 14-18 weeks of age with these gene signatures overlapping significantly with those seen in lungs of patients with SSc with interstitial lung disease (ILD). These changes were also evident in the histopathology which showed perivascular and peribronchiolar inflammation with prominent eosinophilia and accumulation of profibrotic M2-like macrophages followed by rapid progression to fibrosis with thickened alveolar walls with multifocal-fibrotic-bands and signs of interstitial-pneumonia. Critically, treatment with a bispecific antibody targeting IL-4 and IL-13 during the inflammatory phase abrogated the Th2 and M2-responses and led to near complete abrogation of lung fibrosis. These data recapitulate important features of fibrotic-progression in lungs of SSc-ILD patients and enhance our understanding of the progressive pathobiology of SSc. This study also further establishes FRA2-Tg mice as a valuable tool for testing future therapeutic agents in SSc-ILD.