Extracellular matrix and immune dysfunction: An overlooked relationship in idiopathic pulmonary fibrosis

Idiopathic pulmonary fibrosis (IPF) is a progressive fatal disease. Current clinically approved treatments slow disease progression but are not curative. Thus, there is a critical need to better define the pathogenic mechanisms of IPF and develop novel approaches to treat this devastating lung condition. Immune dysregulation of both the innate and adaptive immune systems, accompanied by fibrosis, constitutes a key hallmark of IPF. IPF is generally considered to be a fibroproliferative disorder rather than an immune condition because, historically, immunomodulatory therapies have failed to produce significant clinical effect. This lack of response is frustrating given that there is evidence of immune dysfunction in IPF and highlights the need to clarify the role of immune cells and inflammatory pathways in IPF. There is increasing evidence that the extracellular matrix (ECM) directs cell fate and function, and we propose that ECM remodeling and immune dysfunction in IPF generate a self-perpetuating fibrotic circuit that is refractory to classical anti-inflammatory agents. Understanding the relationship between ECM and immune dysfunction in IPF pathogenesis could help identify novel therapeutic approaches for this devastating disease.