Role of GM-CSF and IRF5 in steroid refractory asthma (P6247)

Abstract

Abstract Asthma is a heterogeneous, inflammatory disease of the airways characterized by reversible airflow obstruction and bronchoconstriction. 10% of asthma patients are categorized as severe asthmatics (SA), showing mixed neutrophilic/eosinophilic infiltrate, which is poorly responsive to corticosteroids (CS). Elevated levels of inflammatory cytokines, including GM-CSF, IL-6 and IL-17, are found in the airways of SA. Recently, GM-CSF alone or in combination with LPS, was shown to augment expression of IRF5 in macrophages (Mϕ), promoting Th17-driving cytokines. These observations led us to hypothesize that GM-CSF plays an important role in mediating CS-refractory IL-6 production from Mϕ. In RAW 264.7 cells, LPS-induced IL-6 production was inhibited 65% by CS. However, when LPS was combined with GM-CSF at 20 or 200 ng/ml, CS poorly suppressed IL-6 production (17 % and 10.5% respectively). IRF5 expression was detected in LPS+GM-CSF-treated RAW cells and its expression was augmented in the lung-draining lymph nodes of mice exposed to the allergen, house dust mite. Interestingly, IRF5 expression was significantly higher in bronchoalveolar lavage cells isolated from human SA as compared to that in cells from milder, CS-responsive asthmatics or from healthy controls. These observations suggest an important role of GM-CSF and IRF5 in mediating CS-refractory IL-6 production in innate immune cells that in turn promote CS-unresponsive Th17 development and neutrophilic airway inflammation.