Targeting a macrophage stemness factor to mitigate diseases post respiratory viral infection.

Tissue-resident alveolar macrophages (AMs) rely on intrinsic stem-like programs for self-renewal and maintenance, yet the transcriptional networks that support these functions and their relevance to post-viral lung disease remain largely unknown. Here, we identify TCF4 (Tcf7l2) as a critical transcription factor that governs AM maturation and stemness. Loss of TCF4 impaired AM proliferation, shifted their identity toward a pro-inflammatory phenotype, and exacerbated host morbidity following influenza or SARS-CoV-2 infection. Conversely, enforced TCF4 expression promoted the expansion of mature AMs, and supported lung recovery, thereby protecting against severe acute viral disease. Mechanistically, TCF4 antagonized β-catenin-driven inflammatory transcription while preserving oxidative phosphorylation, defining a reciprocal regulatory axis essential for AM function. Notably, respiratory viral infections and exuberant interferon signaling suppressed TCF4 expression, which remains chronically reduced in murine and human lungs with post-COVID fibrosis. This downregulation is associated with persistent KRT8hi dysplastic epithelium and collagen deposition. Moreover, aging diminished TCF4 levels and enforced TCF4 expression dampened age-associated decline of AM self-renewal. Furthermore, in vivo TCF4 overexpression after viral clearance enhanced mature AM accumulation, promoted lung epithelium regeneration, attenuated chronic tissue fibrosis and restored pulmonary physiologial function in aged lungs in a model of persistent pulmonary fibrosis post-acute viral infection. These findings have established TCF4 as a key regulator of AM stemness and identified a promising therapeutic target for long COVID and related chronic lung diseases through the modulation of embryonic-derived macrophage regenerative capacity by targeting TCF4.