Alveolar-Basal Intermediates Drive Pulmonary Fibrosis via Coordination of a Pro-Fibrotic Signaling Niche in Silicosis
Pulmonary fibrosis is a progressive, terminal disease with high morbidity. Existing therapeutics slow disease progression but do not reverse fibrotic lung remodeling, accentuating the importance of identifying cellular mechanisms that underlie lung fibrosis. Recent literature suggests that alveolar type 2 (AT2) progenitors undergo transition to stressed Krt8high cells following lung injury. Accumulation of stressed Krt8high cells is a hallmark of acute and chronic lung diseases, particularly pulmonary fibrosis. Whether Krt8high cells actively participate in the fibrotic process or are simply an epiphenomenon of lung injury remains unclear. We previously described a genetic model in which deletion of the lung transcription factor Nkx2-1 in the AT2 progenitor lineage induces AT2 progenitors to transition to the Krt8high cell state. Here, we use this tractable genetic model to directly test the pathogenic influence of Krt8high cells. We show that Nkx2-1-/- Krt8high cells accumulate in a Krt7high/Krt19high/Krt17neg alveolar-basal intermediate cell state (ABI). Following induction of fibrotic lung injury with inhaled silica, ABI enter a unique inflammatory state (iABI) that drives fibrotic remodeling via coordination of a fibrotic signaling niche containing inflammatory alveolar fibroblasts (iAF) and pulmonary osteoclast-like cells (POLC). Computational analysis predicts that iABI elaborate pro-inflammatory signals which increase matrix deposition by iAF and induce differentiation of interstitial macrophages to a profibrotic POLC variant. Niche mapping demonstrates that iABI, iAF, and POLCs interact within newly formed fibrotic niches in the lung alveolus in mice with pre-existing accumulation of ABI. These data provide direct evidence that ABI accumulation in fibrotic lung disease is pathogenic.