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Mucosal Immunol. 2020 Mar 9. doi: 10.1038/s41385-020-0280-z. [Epub ahead of print]

NMP4 regulates the innate immune response to influenza A virus infection.

Author information

1
Department of Pediatrics, Herman B Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, IN, USA.
2
Department of Microbiology and Immunology, Indiana University School of Medicine, Indianapolis, IN, USA.
3
Department of Anatomy, Cell Biology & Physiology, Indiana University School of Medicine, Indianapolis, IN, USA.
4
Thoracic Diseases Research Unit, Division of Pulmonary and Critical Care, Department of Medicine, Mayo Clinic College of Medicine, Rochester, MN, USA.
5
Department of Oral and Craniofacial Sciences, School of Dentistry, University of Missouri Kansas City, Kansas City, MO, 64108, USA.
6
Department of Anatomy, Cell Biology & Physiology, Indiana University School of Medicine, Indianapolis, IN, USA. jbidwell@iu.edu.
7
Department of Pediatrics, Herman B Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, IN, USA. zhoub@iu.edu.
8
Department of Microbiology and Immunology, Indiana University School of Medicine, Indianapolis, IN, USA. zhoub@iu.edu.

Abstract

Severe influenza A virus infection typically triggers excessive and detrimental lung inflammation with massive cell infiltration and hyper-production of cytokines and chemokines. We identified a novel function for nuclear matrix protein 4 (NMP4), a zinc-finger-containing transcription factor playing roles in bone formation and spermatogenesis, in regulating antiviral immune response and immunopathology. Nmp4-deficient mice are protected from H1N1 influenza infection, losing only 5% body weight compared to a 20% weight loss in wild type mice. While having no effects on viral clearance or CD8/CD4 T cell or humoral responses, deficiency of Nmp4 in either lung structural cells or hematopoietic cells significantly reduces the recruitment of monocytes and neutrophils to the lungs. Consistent with fewer innate cells in the airways, influenza-infected Nmp4-deficient mice have significantly decreased expression of chemokine genes Ccl2, Ccl7 and Cxcl1 as well as pro-inflammatory cytokine genes Il1b and Il6. Furthermore, NMP4 binds to the promoters and/or conserved non-coding sequences of the chemokine genes and regulates their expression in mouse lung epithelial cells and macrophages. Our data suggest that NMP4 functions to promote monocyte- and neutrophil-attracting chemokine expression upon influenza A infection, resulting in exaggerated innate inflammation and lung tissue damage.

PMID:
32152414
DOI:
10.1038/s41385-020-0280-z

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