After the Storm: Regeneration, Repair, and Reestablishment of Homeostasis Between the Alveolar Epithelium and Innate Immune System Following Viral Lung Injury

Abstract

The mammalian lung has an enormous environmental-epithelial interface that is optimized to accomplish the principal function of the respiratory system, gas exchange. One consequence of evolving such a large surface area is that the lung epithelium is continuously exposed to toxins, irritants, and pathogens. Maintaining homeostasis in this environment requires a delicate balance of cellular signaling between the epithelium and innate immune system. Following injury, the epithelium can be either fully regenerated in form and function or repaired by forming dysplastic scar tissue. In this review, we describe the major mechanisms of damage, regeneration, and repair within the alveolar niche where gas exchange occurs. With a focus on viral infection, we summarize recent work that has established how epithelial proliferation is arrested during infection and how the innate immune system guides its reconstitution during recovery. The consequences of these processes going awry are also considered, with an emphasis on how this will impact postpandemic pulmonary biology and medicine.

Keywords: alveolar epithelial cell; immune-epithelial interactions; influenza; regeneration; repair.

Figure 1

(a) Epithelium of the lower airway and composition of the alveolus. (b) Repair and regeneration of the alveolus following injury. At homeostasis, the alveolar epithelium consists of squamous alveolar type 1 epithelial cells that are located in close contact with the capillary bed to facilitate gas exchange, as well as cuboidal alveolar type 2 epithelial cells that secrete surfactant stored in lamellar bodies. The alveolus is surrounded by a sparse interstitium composed of fibroblasts, interstitial macrophages, and other cell types not depicted here (e.g., lymphatic vessels and nerves). Viral injury causes alveolar epithelial cell death, barrier dysfunction, impaired gas exchange, alveolar hemorrhage, and infiltration of leukocytes and protein-rich fluid. Resolution of inflammation can occur via regeneration (reconstitution of the functional alveolus) or repair (scarring). Repaired epithelium does not participate in gas exchange and contains airway-derived cuboidal epithelial cells expressing Krt5+. Abbreviation: Krt5, keratin 5. Figure adapted from images created with BioRender.

Figure 2

Alveolus intrinsic signals that promote proliferation and differentiation. AT2 cells serve as facultative progenitors for the alveolar epithelium. Recent work has uncovered subpopulations of AT2 cells that are preferentially endowed with proliferative capacity. AT2 cells are capable of regenerating both AT2 and AT1 lineages via proliferation and differentiation, respectively. Recent work has identified extracellular signals that promote (fibroblast growth factors, interleukin 1) or restrict (Tgf-β, interferons) AT2 cell proliferation. In contrast, Tgf-β promotes differentiation of AT2 cells into AT1 cells, while intracellular Yap/Taz signaling actively maintains AT1 identity by preventing differentiation back to the AT2 lineage. Abbreviations: AT1, alveolar type 1; AT2, alveolar type 2; Taz, transcriptional coactivator with PDZ-binding motif; Tgf-β, transforming growth factor beta; Yap, Yes-associated protein. Figure adapted from images created with BioRender.

Figure 3

Immune signaling in the alveolus. At homeostasis, the alveolus is maintained in a quiescent state via bidirectional signaling between the alveolar epithelium and alveolar macrophages. These mechanisms include production of soluble factors such as IL-1, which is secreted by myeloid immune cells and promotes AT2 cell proliferation via the IL-1 receptor. GM-CSF is secreted by AT2 cells and signals via PPAR-γ to induce a transcriptional program that promotes surfactant homeostasis. AT2s also express the cell surface ligand CD200, which provides immunoregulatory signals to alveolar macrophages via CD200R. Several recent studies have also shown coordinated calcium-mediated signaling via gap junctions (notably connexin 43). Abbreviations: AT2, alveolar type 2; GM-CSF, granulocyte-macrophage colony-stimulating factor; IL, interleukin; PPAR, peroxisome proliferator-activated receptor. Figure adapted from images created with BioRender.