Immune dysregulation as a driver of idiopathic pulmonary fibrosis

Abstract

Idiopathic pulmonary fibrosis (IPF) affects hundreds of thousands of people worldwide, reducing their quality of life and leading to death from respiratory failure within years of diagnosis. Treatment options remain limited, with only two FDA-approved drugs available in the United States, neither of which reverse the lung damage caused by the disease or prolong the life of individuals with IPF. The only cure for IPF is lung transplantation. In this review, we discuss recent major advances in our understanding of the role of the immune system in IPF that have revealed immune dysregulation as a critical driver of disease pathophysiology. We also highlight ways in which an improved understanding of the immune system's role in IPF may enable the development of targeted immunomodulatory therapies that successfully halt or potentially even reverse lung fibrosis.

Trial registration: ClinicalTrials.gov NCT00125385 NCT03573505.

Figure 1. In individuals with idiopathic pulmonary fibrosis, lung epithelial injury leads to production of profibrotic cytokines and chemokines such as CCL18, CHI3L1, MMPs, Wnt, and TGF-β by alveolar macrophages.

This results in activation of fibroblasts and differentiation into myofibroblasts, which produce extracellular matrix leading to thickening of the lung interstitium. Abnormal epithelial-mesenchymal transition (EMT) also contributes to the pool of myofibroblasts in the lung interstitium. Regulatory T cells inhibit Th1 cell activation, resulting in an altered Th1/Th2 balance in the lung. Production of IL-4 and IL-13 by Th2 cells promotes polarization of alveolar macrophages into an M2 profibrotic phenotype and differentiation of circulating fibrocytes into fibroblasts. IL-17 production by Th17 cells in the lung also promotes fibroblast activation. CD8⁺ T cells and TRM CD4⁺ T cells appear to protect against fibrosis, although the mechanisms through which they do so are not well understood.