Tonic interferon restricts pathogenic IL-17-driven inflammatory disease via balancing the microbiome.

Isabelle J Marié,Azlann Arnett,Haiyan S Li,Ze Chen,Doua Azzouz,Gisele V Baracho,Weiguo Liu,Pratip Chattopadhyay,David E Levy,Lara Brambilla,Luisa Cimmino,Stephanie S Watowich,Gregg Silverman,Bernard Khor

doi:10.7554/elife.68371

Abstract

Maintenance of immune homeostasis involves a synergistic relationship between the host and the microbiome. Canonical interferon (IFN) signaling controls responses to acute microbial infection, through engagement of the STAT1 transcription factor. However, the contribution of tonic levels of IFN to immune homeostasis in the absence of acute infection remains largely unexplored. We report that STAT1 KO mice spontaneously developed an inflammatory disease marked by myeloid hyperplasia and splenic accumulation of hematopoietic stem cells. Moreover, these animals developed inflammatory bowel disease. Profiling gut bacteria revealed a profound dysbiosis in the absence of tonic IFN signaling, which triggered expansion of TH17 cells and loss of splenic Treg cells. Reduction of bacterial load by antibiotic treatment averted the TH17 bias and blocking IL17 signaling prevented myeloid expansion and splenic stem cell accumulation. Thus, tonic IFNs regulate gut microbial ecology, which is crucial for maintaining physiologic immune homeostasis and preventing inflammation.

Highlights

Interferons (IFNs) are important mediators of innate and adaptive immunity
We observed that STAT1 deficient animals developed a spontaneous splenomegaly irrespective of age and sex
(p=0.000029), was dramatically increased in STAT1 KO mice compared to wild type (WT)

Summary

Introduction

Interferons (IFNs) are important mediators of innate and adaptive immunity. The generic term IFN comprises three types of cytokines: Type I family (IFN-I) encoded by multiple genes, including primarily numerous IFN- subtypes and IFN- ; type II family (IFN-II), with IFN- being its sole member; and type III (IFN-III) family consisting of several IFN43 s. Each IFN family signals through a distinct heterodimeric cell surface receptor. All members of IFN-I bind a receptor termed IFNAR, which triggers activation of the Jak kinases Jak and Tyk that mediate tyrosine phosphorylation of two members of the signal transducer and activator of transcription (STAT) family, STAT1 and STAT2. IFN-II, after binding its cognate receptor (IFNGR), signals predominately through homodimers of STAT1 and stimulates a set of genes containing a gamma-activating sequence (GAS) [3]. All these pathways converge on STAT1, and STAT1 deficiency or hypofunction leads to insensitivity to all types of IFN. Individuals with STAT1 gain-offunction (GOF) mutations suffer most frequently from mucocutaneous diseases, in part due to depressed levels of TH17 cells, thereby attributing important regulatory functions to STAT1 [9, 10]

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Conclusion