Regulation of epithelial transitional states in murine and human pulmonary fibrosis

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 (KRT) 8 genetic variants are associated with IPF. Krt8-/- mice are protected from fibrosis and accumulation of the transitional state. Keratin (K) 8 regulates expression of macrophage chemokines and macrophage recruitment. Profibrotic macrophages and myofibroblasts promote accumulation of transitional AECs, establishing a K8-dependent positive feedback loop driving fibrogenesis. Finally, rare murine transitional AECs are highly senescent, basaloid, and do not differentiate into AEC1s, recapitulating the aberrant basaloid state in human IPF. We conclude that transitional AECs induce and are maintained by fibrosis in a K8-dependent manner; in mice, most transitional cells and fibrosis resolve, whereas in human IPF, transitional AECs evolve into an aberrant basaloid state which persists with progressive fibrosis.