Targeted deletion of NFAT-Interacting-Protein-(NIP) 45 resolves experimental asthma by inhibiting Innate Lymphoid Cells group 2 (ILC2)

• Published in: Scientific reports 2019-10, Vol.9 (1), p.15695-14, Article 15695
• Main Authors: Koch, Sonja, Knipfer, Lisa, Kölle, Julia, Mirzakhani, Hooman, Graser, Anna, Zimmermann, Theodor, Kiefer, Alexander, Melichar, Volker O., Rascher, Wolfgang, Papadopoulos, Nikolaos G., Rieker, Ralf J., Raby, Benjamin A., Weiss, Scott T., Wirtz, Stefan, Finotto, Susetta
• Format: Article
• Language: English
• Subjects: 38; 38/77; 64; 64/60; 692/1807/1809; 692/4017; 692/420/256/2515; Allergies; Animals; Asthma; Asthma - genetics; Asthma - metabolism; Asthma - pathology; Bone marrow; Carrier Proteins - genetics; CD4 antigen; Cell differentiation; Cell number; Child; Child, Preschool; Children; Clonal deletion; Disease Models, Animal; Female; GATA-3 protein; Gene deletion; Humanities and Social Sciences; Humans; Immunity, Innate - genetics; Interleukin-33 - genetics; Leukocytes (eosinophilic); Leukocytes (mononuclear); Leukocytes, Mononuclear - immunology; Leukocytes, Mononuclear - metabolism; Lung - immunology; Lung - metabolism; Lung - pathology; Lymphocytes - immunology; Lymphocytes - metabolism; Lymphocytes T; Lymphoid cells; Male; Mice; Mice, Knockout; Mucus - immunology; Mucus - metabolism; multidisciplinary; NF-AT protein; NFATC Transcription Factors - genetics; Peripheral blood mononuclear cells; Phenotypes; Respiratory Hypersensitivity - genetics; Respiratory Hypersensitivity - immunology; Respiratory tract; Science; Science (multidisciplinary); Spleen; T-Box Domain Proteins - genetics; Therapeutic applications; Transcription factors
• ISSN: 2045-2322; 2045-2322
• DOI: 10.1038/s41598-019-51690-z

Here we investigated the role of NFAT-interacting protein (NIP)-45, an Interleukin (IL)-4 inducing Transcription Factor, and its impact on the differentiation of Group 2 Innate -Lymphoid -Cells (ILC2s) in the pathogenesis of asthma. NIP45 , a transcription factor regulating NFATc1 activity, mRNA was found to be induced in the Peripheral Blood mononuclear cells (PMBCs) of asthmatic pre-school children with allergies and in the peripheral blood CD4 + T cells from adult asthmatic patients. In PBMCs of asthmatic and control children, NIP45 mRNA directly correlated with NFATc1 but not with T-bet. Targeted deletion of NIP45 in mice resulted in a protective phenotype in experimental asthma with reduced airway mucus production, airway hyperresponsiveness and eosinophils. This phenotype was reversed by intranasal delivery of recombinant r-IL-33. Consistently, ILC2s and not GATA3 + CD4 + T-cells were decreased in the lungs of asthmatic NIP45 −/− mice. Reduced cell number spleen ILC2s could be differentiated from NIP45 −/− as compared to wild-type mice after in vivo injection of a microcircle-DNA vector expressing IL-25 and decreased cytokines and ILC2 markers in ILC2 differentiated from the bone marrow of NIP45 −/− mice. NIP45 thus emerges as a new therapeutic target for the resolution of the airway pathology, down-regulation of ILC2s and mucus production in asthma.