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

Sonja Koch,Nikolaos G Papadopoulos,Alexander Kiefer,Benjamin A Raby,Hooman Mirzakhani,Stefan Wirtz,Susetta Finotto,Ralf J Rieker,Volker O Melichar,Anna Graser,Julia Kölle,Theodor Zimmermann,Scott T Weiss,Wolfgang Rascher,Lisa Knipfer

doi:10.1038/s41598-019-51690-z

Abstract

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.

Highlights

We investigated the role of nuclear factor of activated T cells (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 was found significantly induced in asthmatic pre-school children with self-reported atopic eczema and positive skin test (Fig. 1c,d, respectively), to what we recently reported for NFATc1 expression in these cohorts of children
We demonstrate that asthmatic pre-school children at the age of 4–6 years as well as adult asthmatics have a significantly increased expression of NIP45 in the peripheral blood, compared to healthy children and adults, indicating that NIP45 plays an important role in the pathogenesis of asthma

Summary

Introduction

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. It has been previously shown that in the absence of NFATc2, the differentiation of Th1 cells is diminished, while the development of Th2 cells and IL-4 production is up-regulated, especially in a model of allergic asthma[9,13]. The loss of both NFATc2 and NFATc3 leads to increased expression of Th2 cytokines as well as to high IgG1 and IgE levels[14,15,16,17]. The phenotype of NFAT deficient mice does not reflect differences in DNA-binding or transcriptional activity at the IL-4 promoter, but most likely indicates interactions with other regulating transcription factors or other indirect effects

Objectives

Methods

Results

Conclusion