Leukotriene B4 Receptor 2 Mediates the Production of G-CSF That Plays a Critical Role in Steroid-Resistant Neutrophilic Airway Inflammation

Abstract

Granulocyte colony-stimulating factor (G-CSF) has been suggested to be closely associated with neutrophilic asthma pathogenesis. However, little is known about the factors regulating the production of G-CSF in neutrophilic asthma. We previously reported that a leukotriene B4 receptor 2, BLT2, played an important role in neutrophilic airway inflammation. Therefore, in the current study, we investigated whether BLT2 plays a role in the production of G-CSF in lipopolysaccharide/ovalbumin (LPS/OVA)-induced steroid-resistant neutrophilic asthma. The data showed that BLT2 critically mediated G-CSF production, contributing to the progression of neutrophilic airway inflammation. We also observed that 12-lipoxygenase (12-LO), which catalyzes the synthesis of the BLT2 ligand 12(S)-HETE, was also necessary for G-CSF production. Together, these results suggest that the 12-LO-BLT2-linked signaling network is critical for the production of G-CSF, contributing to the development of neutrophilic airway inflammation. Our findings can provide a potential new target for the therapy of severe neutrophilic asthma.

The Genomic Architecture of Circulating Cytokine Levels Points to Drug Targets for Immune-Related Diseases

“…Furthermore, the association between genetically proxied IL-1 receptor antagonist (IL-1ra) levels and lower risk of RA reached a PPA of 68% for a shared causal variant in colocalization analysis. These results are consistent with data from preclinical studies, [46][47][48] observational studies in humans, [49][50][51][52][53] and clinical trials, 54,55 thus providing support for potentially promising targeted immunotherapies for these indications.…”

“…46,56 Several preclinical studies in asthma models showed that blockage of upstream inductors or the receptor of G-CSF/CSF-3 reduced circulating cytokine levels, alleviated the airway inflammatory response, and improved disease outcome. [46][47][48]57 Furthermore, G-CSF/CSF-3 levels in the sputum of asthma patients have been suggested as a marker of airway neutrophilic inflammation. 58 Our results provide genetic support for the concept of targeting G-CSF/CSF-3 in asthma, potentially focusing on patients with neutrophilic asthma.…”