NMP4 regulates innate immune responses to influenza A virus infection

Abstract

Abstract Severe influenza A virus infection typically triggers excessive and detrimental lung inflammation with massive cell infiltration and hyper-production of cytokines and chemokines. Defining research models to alleviate lung damage without compromising viral control is critical. We identified a novel function for nuclear matrix protein 4 (NMP4), a zinc-finger-containing transcription factor in regulating lung inflammation and antiviral innate immune responses. Nmp4-deficient mice are protected from H1N1 influenza infection, losing less body weight compared to the wild-type mice. Nmp4-deficiency does not affect viral clearance or adaptive immune responses, but significantly reduces the accumulation of neutrophils and monocytes in the lungs and the early inflammation. Consistent with fewer innate cells in the airways, infected Nmp4-deficient mice show decreased expression of chemokine genes Ccl2 and Cxcl1 as well as pro-inflammatory cytokine genes Il1b and Il6. We further reveal that NMP4 binds to the promoters and/or conserved non-coding sequences (CNS) of Ccl2 and Cxcl1 in mouse lung epithelial cells. Besides, the knockdown of NMP4 by CRISPR/Cas9 or siRNA significantly lessens the luciferase activities of Ccl2 and Cxcl1 promoters and/or CNS. Taken together, our data suggest that NMP4 regulates monocyte- and neutrophil-attracting chemokine expression in airway epithelial cells upon influenza infection, resulting in exaggerated innate inflammation and lung tissue damage.