ELife: T Interferon Suppresses Inflammatory Diseases by Balancing the Microbiome

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Posted on: 26 October 2021 by chen shanshan

ELife: T Interferon Suppresses Inflammatory Diseases by Balancing the Microbiome

The maintenance of immune homeostasis involves a synergistic relationship between the host and the microbiome. Canonical interferon (IFN) signaling controls the response to acute microbial infection through the involvement of STAT1 transcription factors. However, the contribution of tonic levels of interferon to immune homeostasis in the absence of acute infection remains largely unexplored. The authors report that STAT1KO mice spontaneously develop inflammatory diseases characterized by bone marrow hyperplasia and splenic accumulation of hematopoietic stem cells. In addition, these animals developed inflammatory bowel disease. Analysis of intestinal bacteria revealed severe dysbiosis in the absence of potent IFN signaling, which triggers expansion of TH17 cells and loss of splenic Treg cells. Reduction of bacterial burden by antibiotic treatment avoids TH17 bias, and blockade of IL17 signaling prevents medullary expansion and splenic stem cell accumulation. Thus, tonic interferons modulate gut microbial ecology, which is essential to maintain physiological immune homeostasis and prevent inflammation.

 

Interferon (IFN) is an important mediator of innate and adaptive immunity. Interferons are generally composed of three types of cytokines: type I interferon family encoded by a variety of genes, mainly including a variety of interferon-α subtypes and interferon-β; type II interferon family, of which interferon-γ is its only member; type III interferon family consists of several interferon-λ, and each interferon family signals through a different heterodimeric cell surface receptor.

All members of interferon-I bind a receptor called IFNAR that triggers the activation of the JAK kinases JAK1 and Tyk2, which mediate tyrosine phosphorylation of two members of the signal transducer and activator of transcription (STAT) family, STAT1 and STAT2. Activated STAT1 and STAT2, together with interferon regulatory factor (IRF) 9, form the heterotrimeric complex ISGF3 that binds to interferon-stimulated response elements in the promoters of hundreds of interferon-stimulated genes. This signaling cascade also activates ISGF3 when IFN-III binds to different receptors composed of IL28Ra and IL10Rb subunits and largely overlaps with pathways downstream of IFN-I. In contrast, IFN-II signals mainly through homodimers of STAT1 after binding its cognate receptor (IFNGR) and stimulates a set of genes containing gamma-activating sequences (GAS). All of these pathways are focused on STAT1, and STAT1 deficiency or hypofunction results in insensitivity to all types of interferons. As expected, STAT1 deficiency in humans results in increased susceptibility to viral and mycobacterial infections, and hematopoietic cell transplantation remains the only therapeutic approach.

Patients lacking STAT1 are unable to thrive in the absence of an appropriate innate immune response to microbes, which precludes studies of the contribution of STAT1 in homeostasis. However, some patients with partial loss of STAT1 function (LOF) have chronic colitis, as well as severe infections. On the other hand, individuals with enhanced STAT1 function (GOF) mutations most commonly suffer from mucocutaneous disease, in part due to reduced levels of TH17 cells, thereby attributing important regulatory functions to STAT1.

 

Despite being involved in similar downstream signaling cascades, it is becoming increasingly evident that interferon-I and -III play different roles in establishing innate immunity to microbes and participate in the overall immune function of the host in different ways. For example, interferon-III has been shown to reduce inflammation by reducing the number of IL-17-producing TH17 helper T cells and limiting neutrophil recruitment. Interestingly, in addition to its important role in inflammation, IL-17 also plays an important role in hematopoiesis. For example, IL-17 stimulates myeloid and erythroid progenitors, suggesting that IFN-III may play a role in hematopoietic regulation by limiting the action of IL-17. In addition, due in part to the more limited distribution of their receptors, IFN-III members display a unique ability to fight pathogen invasion at mucosal sites while inhibiting excessive inflammation, helping to maintain barrier integrity.

Accumulating evidence suggests that commensal gut microflora present on mucosal surfaces also play an important role in shaping the host immune system. However, the understanding of the importance of the interaction between microbial IFNs to prevent pathogenesis is limited. Here, the authors reveal a role for STAT1 in controlling microbial ecology that prevents inflammation and maintains immune homeostasis in the absence of infectious challenges. The study suggests that tetanic signaling through the IFN pathway acting through its common mediator STAT1 is an essential modulator of immune homeostasis, reducing the inflammatory predisposition. This tonic IFN signaling appears to involve all three major IFN families, as loss of all three branches of the pathway is required for an intact inflammatory phenotype. Lack of tonic interferon signaling can form a distorted microbiome, which triggers an inflammatory response that may result from a biased increase in TH17 cells to pathogenic phenotypes, as well as impaired homing or survival of peripheral Treg.

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