Platelets: inflammatory effector cells in the conflagration of cystic fibrosis lung disease

Abstract

Cystic fibrosis (CF) is a multisystem disorder, but progressive inflammatory lung disease causes the greatest burden of morbidity and death. Recent translational and mechanistic studies of samples from patients, and observations in animal models, indicate that platelets may drive lung injury and contribute to dysregulated host defense in CF lung disease. In this issue of the JCI, Ortiz-Muñoz and Yu et al. explored the role that the cystic fibrosis transmembrane conductance regulator (CFTR) plays in platelet-related inflammation. The authors used mouse and human model systems to show that CFTR dysfunction in platelets increased calcium entry though the transient receptor potential cation channel 6 (TRPC6), causing hyperactivation and consequent experimental lung inflammation. The study persuasively suggests that platelets are critical thromboinflammatory effector cells in CF lung disease. In the context of platelet-related organ injury seen in a variety of other diseases and syndromes, platelets may also contribute to nonpulmonary manifestations and comorbidities of CF.

Figure 1. Model for platelets as inflammatory effector cells in the conflagration of cystic fibrosis lung disease.

Defective CFTR induces increased calcium influx through TRPC6, resulting in hyperactivation of platelets when they are stimulated by inflammatory and prothrombotic agonists. Consequent binding of P selectin to PSGL-1 on neutrophils and other leukocytes contributes to thromboinflammatory injury in multiple organs and systems relevant to CF. Other effector responses of activated platelets, including adhesive interactions via integrin α_llbβ₃ and signaling of NET formation, may also contribute to CF complications and comorbidities.