Immune mechanisms in fibrotic interstitial lung disease

Abstract

Fibrotic interstitial lung diseases (fILDs) have poor survival rates and lack effective therapies. Despite evidence for immune mechanisms in lung fibrosis, immunotherapies have been unsuccessful for major types of fILD. Here, we review immunological mechanisms in lung fibrosis that have the potential to impact clinical practice. We first examine innate immunity, which is broadly involved across fILD subtypes. We illustrate how innate immunity in fILD involves a complex interplay of multiple cell subpopulations and molecular pathways. We then review the growing evidence for adaptive immunity in lung fibrosis to provoke a re-examination of its role in clinical fILD. We close with future directions to address key knowledge gaps in fILD pathobiology: (1) longitudinal studies emphasizing early-stage clinical disease, (2) immune mechanisms of acute exacerbations, and (3) next-generation immunophenotyping integrating spatial, genetic, and single-cell approaches. Advances in these areas are essential for the future of precision medicine and immunotherapy in fILD.

Keywords: fibroblasts; idiopathic pulmonary fibrosis; immune system; interstitial lung diseases; pulmonary fibrosis.

Figure 1.. Fibrosing interstitial lung disease (fILD).

A. In fILD alveolar injury and abnormal repair leads to fibroblast accumulation, extracellular matrix deposition, and fibrosis of the interstitial spaces. The resulting end-stage “honeycombing” is seen in: B. lung histology; and C. high resolution chest CT imaging. B, C: images are obtained by authors.

Figure 2.. Research methods in lung fibrosis.

Human samples for translational studies of patients with fibrotic lung interstitial lung disease include bronchoalveolar lavage fluid (BAL), lung tissue obtained during biopsy or explant, and blood. Biobanked specimens can be analyzed by “omic” approaches, while primary cells may be isolated from fresh tissue samples for conventional two-dimensional tissue culture studies or three-dimensional organoids or complex in vitro model systems like “lung on a chip”. Lung tissue can also be used to generate precision cut lung slices (PCLS). Animal models induce lung fibrosis via bleomycin or silica exposure.

Figure 3.. Immune and stromal cell interactions drive fibrosis in fILD.

Epithelial cells exhibit aberrant repair responses after recurrent injury in the setting of risk factors like age, smoke exposure, or increased cell senescence. The dysfunctional epithelial cells profibrotic mediators, leading to a cascade of cell-cell interactions among the epithelium, endothelium, mesenchyme, and immune system drives lung fibrosis (i.e., deposition of extracellular matrix [ECM] in the lung interstitium by myofibroblasts). In addition to the proliferation of fibroblasts, the transition of type 2 alveolar epithelial cells (AT2) and endothelial cells (EMT and Endo-MT, respectively) to mesenchymal cells contribute to the accumulation of fibroblasts.

Figure 4.. Th1/2, M1/M2, and Th17 axes in fILD.

A. Naive T cells, also known as T-helper type 0 (Th0) cells, can differentiate into Th1 (via stimulation by IL-12) or Th2 cells (via IL-4). Th1 cells are on balance protective against lung fibrosis. Th1 cells promote M1 and inhibit M2 phenotypes in macrophages. M1 macrophages contribute to pathogenesis pathogenic by prolonged production of IL-1β that inhibits healthy epithelial cell renewal and inflammatory stimulation of fibroblast migration and proliferation. Th2 cells are pathogenic and drive M2 phenotypes. M2 macrophages secrete TGF-β that promotes the differentiation of fibroblasts into myofibroblasts producing ECM. B. Th17 cells are pathogenic and produce IL-17 that activates neutrophils and augments EMT. These mesenchymal cells migrate, proliferate, and differentiate into myofibroblasts producing ECM.