Strong toll-like receptor responses in cystic fibrosis patients are associated with higher lung function

•Cystic fibrosis (CF) is characterized by chronic airway infection and inflammation that together contribute to progressive decline in lung function, and increased airway inflammation has been associated with worse manifestations of disease.•Toll-like receptors (TLRs) allow innate immune cells to rapidly mount inflammatory responses to pathogenic organisms, including CF-associated bacteria.•Prior studies of TLR-associated responses have shown that peripheral blood monocytes from people with CF demonstrate decreased TLR responses compared to cells from healthy donors.•In these studies we confirm that ex vivo peripheral blood cells from people with CF mount lower inflammatory responses to TLR agonists compared with healthy controls; however, we also demonstrate that more robust TLR-mediated innate immune responses are correlated with better lung function and slower lung function decline in people with CF.•These findings enhance our understanding of the relationship between innate immune responses, lung inflammation, and progression of CF lung disease, and challenge the hypothesis that more robust inflammatory responses will predict more rapid lung function decline. Cystic fibrosis (CF) airways disease varies widely among patients with identical cystic fibrosis transmembrane conductance regulator (CFTR) genotypes. Robust airway inflammation is thought to be deleterious in CF; inter-individual variation in Toll-like receptor (TLR)-mediated innate immune inflammatory responses (TMIIR) might account for a portion of the phenotypic variation. We tested if TMIIR in people with CF are different than those of healthy controls, and whether higher TMIIR in people with CF are associated with reduced lung function. We cultured whole blood from clinically stable subjects with CF (n = 76) and healthy controls (n = 45) with TLR agonists, and measured cytokine production and expression of TLR-associated genes. We tested for differences in TLR-stimulated cytokine levels between subjects with CF and healthy subjects, and for associations between cytokine and gene expression levels with baseline lung function (forced expiratory volume in one second percent predicted (FEV1%)) and decline in FEV1% over time. TMIIR in blood from subjects with CF were lower than in healthy controls. Expression of TLR regulators SARM1, TOLLIP, and AKT1 were downregulated in CF. In subjects with CF we found that lower TLR4-agonist-induced IL-8 was associated with lower FEV1% at enrollment (p