Targeting the human β_c receptor inhibits inflammatory myeloid cells and lung injury caused by acute cigarette smoke exposure

Abstract

Background and objective Chronic obstructive pulmonary disease (COPD) is a devastating disease commonly caused by cigarette smoke (CS) exposure that drives tissue injury by persistently recruiting myeloid cells into the lungs. A significant portion of COPD patients also present with overlapping asthma pathology including eosinophilic inflammation. The βc cytokine family includes granulocyte monocyte‐colony‐stimulating factor, IL‐5 and IL‐3 that signal through their common receptor subunit βc to promote the expansion and survival of multiple myeloid cells including monocytes/macrophages, neutrophils and eosinophils. Methods We have used our unique human βc receptor transgenic (hβcTg) mouse strain that expresses human βc instead of mouse βc and βIL3 in an acute CS exposure model. Lung tissue injury was assessed by histology and measurement of albumin and lactate dehydrogenase levels in the bronchoalveolar lavage (BAL) fluid. Transgenic mice were treated with an antibody (CSL311) that inhibits human βc signalling. Results hβcTg mice responded to acute CS exposure by expanding blood myeloid cell numbers and recruiting monocyte‐derived macrophages (cluster of differentiation 11b+ [CD11b+] interstitial and exudative macrophages [IM and ExM]), neutrophils and eosinophils into the lungs. This inflammatory response was associated with lung tissue injury and oedema. Importantly, CSL311 treatment in CS‐exposed mice markedly reduced myeloid cell numbers in the blood and BAL compartment. Furthermore, CSL311 significantly reduced lung CD11b+ IM and ExM, neutrophils and eosinophils, and this decline was associated with a significant reduction in matrix metalloproteinase‐12 (MMP‐12) and IL‐17A expression, tissue injury and oedema. Conclusion This study identifies CSL311 as a therapeutic antibody that potently inhibits immunopathology and lung injury caused by acute CS exposure.

Contemporary Concise Review 2022: Chronic obstructive pulmonary disease

“…Studying known triggers of disease like cigarette smoke in carefully controlled circumstances can yield new insights. A good example of this approach comes from Fung and colleagues who exposed transgenic mice expressing the human beta c receptor to tobacco smoke and saw an expansion of macrophages, neutrophils and eosinophils, cells relevant to human COPD 14 . They blocked this effect with a monoclonal antibody directed at the receptor which reduced MMP‐12 production, IL‐17A expression and tissue damage.…”

“…A good example of this approach comes from Fung and colleagues who exposed transgenic mice expressing the human beta c receptor to tobacco smoke and saw an expansion of macrophages, neutrophils and eosinophils, cells relevant to human COPD. 14 They blocked this effect with a monoclonal antibody directed at the receptor which reduced MMP-12 production, IL-17A expression and tissue damage. This antibody may be a useful tool to further explore the disease mechanisms in humans.…”

Suppression of long noncoding RNA SNHG6 alleviates cigarette smoke‐induced lung inflammation by modulating NF‐κB signaling

“…1,2 Currently, smoking and secondhand smoke exposure are considered as the major causes of COPD. 3 Numerous clinical treatments are available for COPD; however, persistent and progressive lung inflammation remains common. 4,5 An urgent need therefore exists to explore the mechanisms underlying COPD and identify new therapeutic targets.…”

“…Chronic obstructive pulmonary disease (COPD) is a global disease with a high mortality rate, accompanied by severe chronic bronchitis and emphysema 1,2 . Currently, smoking and secondhand smoke exposure are considered as the major causes of COPD 3 . Numerous clinical treatments are available for COPD; however, persistent and progressive lung inflammation remains common 4,5 .…”