The interplay of DAMPs, TLR4, and proinflammatory cytokines in pulmonary fibrosis

Abstract

Pulmonary fibrosis is a chronic debilitating condition characterized by progressive deposition of connective tissue, leading to a steady restriction of lung elasticity, a decline in lung function, and a median survival of 4.5 years. The leading causes of pulmonary fibrosis are inhalation of foreign particles (such as silicosis and pneumoconiosis), infections (such as post COVID-19), autoimmune diseases (such as systemic autoimmune diseases of the connective tissue), and idiopathic pulmonary fibrosis. The therapeutics currently available for pulmonary fibrosis only modestly slow the progression of the disease. This review is centered on the interplay of damage-associated molecular pattern (DAMP) molecules, Toll-like receptor 4 (TLR4), and inflammatory cytokines (such as TNF-α, IL-1β, and IL-17) as they contribute to the pathogenesis of pulmonary fibrosis, and the possible avenues to develop effective therapeutics that disrupt this interplay.

Keywords: Cytokine; DAMP; Pulmonary fibrosis; TLR4.

Fig. 1

The interplay of DAMPs, TLR4, and proinflammatory cytokines in pulmonary fibrosis centered around macrophages and fibroblasts. (1) Injury to the cells either from a viral infection, chemical/mechanical trauma, or immune-mediated damage causes the release of DAMPs in the microenvironment. (2) DAMPs stimulate and activate macrophages and fibroblasts through a TLR4-MD2 → MyD88-mediated pathway. (3) Activated macrophages release proinflammatory cytokines such as TNF-α, IL-17, and IL-1β in the tissue microenvironment that, (4) along with TGF-β, activate fibroblasts to become profibrotic and deposit collagen and ECM components like fibronectin and tenascin-C. This causes stiffness of ECM and oxidative stress in the microenvironment, which (5) causes the release of more DAMPs leading to the vicious cycle of pulmonary fibrosis. DAMP, damage-associated molecular patterns; HMGB1, high-mobility group box 1; eCIRP, extracellular cold-inducible RNA-binding protein; HSPB5, heat shock protein B5; TLR4, Toll-like-receptor 4; MD2, myeloid differentiation factor 2; MyD88, myeloid differentiation primary response 88; NF-κB, nuclear factor kappa-light-chain-enhancer of activated B cells; ECM, extracellular matrix