Regulation of epithelial transitional states in murine and human pulmonary fibrosis
Fa Wang, … , M. Bishr Omary, Rachel L. Zemans
Fa Wang, … , M. Bishr Omary, Rachel L. Zemans
Published September 28, 2023
Citation Information: J Clin Invest. 2023;133(22):e165612. https://doi.org/10.1172/JCI165612.
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Research Article Pulmonology

Regulation of epithelial transitional states in murine and human pulmonary fibrosis

Abstract

Idiopathic pulmonary fibrosis (IPF) is a progressive scarring disease arising from impaired regeneration of the alveolar epithelium after injury. During regeneration, type 2 alveolar epithelial cells (AEC2s) assume a transitional state that upregulates multiple keratins and ultimately differentiate into AEC1s. In IPF, transitional AECs accumulate with ineffectual AEC1 differentiation. However, whether and how transitional cells cause fibrosis, whether keratins regulate transitional cell accumulation and fibrosis, and why transitional AECs and fibrosis resolve in mouse models but accumulate in IPF are unclear. Here, we show that human keratin 8 (KRT8) genetic variants were associated with IPF. Krt8–/– mice were protected from fibrosis and accumulation of the transitional state. Keratin 8 (K8) regulated the expression of macrophage chemokines and macrophage recruitment. Profibrotic macrophages and myofibroblasts promoted the accumulation of transitional AECs, establishing a K8-dependent positive feedback loop driving fibrogenesis. Finally, rare murine transitional AECs were highly senescent and basaloid and may not differentiate into AEC1s, recapitulating the aberrant basaloid state in human IPF. We conclude that transitional AECs induced and were maintained by fibrosis in a K8-dependent manner; in mice, most transitional cells and fibrosis resolved, whereas in human IPF, transitional AECs evolved into an aberrant basaloid state that persisted with progressive fibrosis.

Authors

Fa Wang, Christopher Ting, Kent A. Riemondy, Michael Douglas, Kendall Foster, Nisha Patel, Norihito Kaku, Alexander Linsalata, Jean Nemzek, Brian M. Varisco, Erez Cohen, Jasmine A. Wilson, David W.H. Riches, Elizabeth F. Redente, Diana M. Toivola, Xiaofeng Zhou, Bethany B. Moore, Pierre A. Coulombe, M. Bishr Omary, Rachel L. Zemans

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Figure 8

Regulation of epithelial transitional states in murine and human pulmonary fibrosis.

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Regulation of epithelial transitional states in murine and human pulmona...
Our current working construct is that after injury, alveolar progenitors assume the K8hi transitional state characterized by the activation of multiple profibrotic processes: senescence, impaired proteostasis, DNA damage, cell death, integrin β6-dependent TGF-β activation, and macrophage chemokine expression. K8 promotes fibrosis by regulating expression of macrophage chemokines, which recruit profibrotic macrophages that further drive fibrosis. Fibroblasts are activated to contract and deposit matrix, stiffening the lung. Stiffness, as well as TGF-β, largely synthesized by macrophages and activated by transitional AEC integrin β6, and IL-1β, synthesized by macrophages, promote accumulation of the AEC transitional state at the expense of AEC1 differentiation. Taken together, our data suggest that crosstalk between K8hi transitional AECs, profibrotic macrophages, and activated fibroblasts maintain each other in an activated state in the lung, establishing a positive feedback loop that drives fibrosis. In the absence of fibrosis, AEC2s may bypass the transitional state and differentiate into AEC1s (dotted line). In mouse models and in humans who recover from acute lung injury, this positive feedback loop is eventually broken, and transitional cells differentiate into AEC1s or perhaps die with resolution of macrophages and activated fibroblasts; in human IPF, the transitional cells further evolve into a permanently senescent, aberrant basaloid state instead of into AEC1s, driving a self-amplifying feedback loop that underlies the progressive and ultimately fatal clinical disease. Adapted from ref. 71 with permission.