Injury-induced pulmonary tuft cells are heterogenous, arise independent of key Type 2 cytokines, and are dispensable for dysplastic repair

Abstract

While the lung bears significant regenerative capacity, severe viral pneumonia can chronically impair lung function by triggering dysplastic remodeling. The connection between these enduring changes and chronic disease remains poorly understood. We recently described the emergence of tuft cells within Krt5+ dysplastic regions after influenza injury. Using bulk and single cell transcriptomics, we characterized and delineated multiple distinct tuft cell populations that arise following influenza clearance. Distinct from intestinal tuft cells which rely on Type 2 immune signals for their expansion, neither IL-25 nor IL-4ra signaling are required to drive tuft cell development in dysplastic/injured lungs. In addition, tuft cell expansion occurred independently of type I or type III interferon signalling. Furthermore, tuft cells were also observed upon bleomycin injury, suggesting that their development may be a general response to severe lung injury. While intestinal tuft cells promote growth and differentiation of surrounding epithelial cells, in the lungs of tuft cell deficient mice, Krt5+ dysplasia still occurs, goblet cell production is unchanged, and there remains no appreciable contribution of Krt5+ cells into more regionally appropriate alveolar Type 2 cells. Together, these findings highlight unexpected differences in signals necessary for murine lung tuft cell amplification and establish a framework for future elucidation of tuft cell functions in pulmonary health and disease.

Respiratory viruses: New frontiers—a Keystone Symposia report

“…9 Tuft cells have also been shown to expand in the lung in response to the influenza virus and SARS-CoV-2. 10,11 Vaughan's lab showed that in the lung, tuft cells arise from Krt5 + a Sci Immunol. 2021 Jan 8;6 (55).…”

“…Vaughan focused on the impact of tuft cells, which are implicated in intestinal damage and repair, where they play a role in type 2 mucosal immunity, characterized by IL‐13, IL‐25, and metaplasia 9 . Tuft cells have also been shown to expand in the lung in response to the influenza virus and SARS‐CoV‐2 10,11 . Vaughan's lab showed that in the lung, tuft cells arise from Krt5 + progenitors.…”

“…Vaughan's lab showed that in the lung, tuft cells arise from Krt5 + progenitors. Unlike in the intestine, lung tuft cells arise independent of type 2 cytokines and have no obvious impact on the development of epithelial dysplasia 10 . Vaughan's group is continuing to work on understanding the signals for injury‐induced lung tuft cell development as well as the role of these cells in lung dysplasia.…”

Chemosensory cells in the respiratory tract as crucial regulators of innate immune responses

“…In a follow up study, Barr and co‐workers characterised these lung ectopic tuft cells on a transcriptional level and were able to delineate different tuft cell populations. The authors found the tuft‐1, tuft‐2 and the undifferentiated population described by Montoro and co‐workers (see ‘Brush cells in the lower airways’) as well as a fourth population that was described as a ‘stressed’ tuft cell population (Barr et al., 2022; Montoro et al., 2018). The ‘stressed’ tuft cell population showed high expression of mitochondrial genes, such as Aqp5 , Hspb1 , Selenbp1 and Cbr2 .…”

“…The tuft‐2 cell population, enriched in genes associated with leukotriene synthesis, was characterised by the expression of the marker genes Alox5ap and Mgst3 . Notably, the post‐influenza lung tuft cells, expressing chemosensory cell markers that can also be found in tracheal brush cells, showed lower levels of Chat and Plcb2 when compared to tracheal brush cells (Barr et al., 2022). While these lung tuft cells show the transcriptional profile of chemosensory cells and, thus, have been identified as members of the chemosensory cell family, their function and role in viral infections remains largely elusive.…”