NOX2-Deficient Pulmonary Neutrophils and Macrophages Have Lower PD-L1 Expression and May Aggravate Allergic Lung Inflammation through Affecting ILC Populations

Abstract

Abstract Redox balance plays an important role in the pathogenesis of allergic asthma. We previously reported that NADPH oxidase 2 (NOX2)-derived ROS may modulate tissue inflammation through affecting neutrophil programmed cell death 1 ligand 1 (PD-L1) expression. To reveal the role of NOX2 in regulating PD-L1 expressions on pulmonary neutrophils and macrophages and in ILC differentiation, we established an allergic asthma model using NOX2-deficient (Cybb−/−)mice stimulated with the Dermatophagoides pteronyssinus(Der p) extract along with LPS. We first found that NOX2 deficiency led to increased group 2 innate lymphoid cell (ILC2) in Der p extract induced lung inflammation. The cell numbers of neutrophil, eosinophil and alveolar macrophage (AM) also increased in the stimulated Cybb−/−mice when compared with WT mice. The AM in Cybb−/−mice expressed higher levels of CD11b and the M2 marker CD163 and produced more TNF-α. Moreover, the Cybb−/−neutrophils and AMs had low PD-L1 expressions while ILC2s had significant levels of programmed cell death 1 (PD-1) expression in the inflammatory lungs. Altogether, these results indicated that NOX2 deficiency may lead to downregulation of PD-L1 expression on neutrophils and AMs while eliciting the M2 phenotype and inducing higher amounts of pro-inflammatory cytokine production. Our results suggested that the lowered PDL1 on NOX2-deficient neutrophils and AMs may aggravate allergic Inflammation through affecting ILC populations in the lung.