They found that STAT1KO mice develop tumors characterized by bone marrow hyperplasia. and splenic accumulation of hematopoietic stem cells.
Maintenance of immune homeostasis involves a. synergistic interaction between the host and the microbiome. Canonical interferon (IFN) signaling regulates. the immune response to acute microbial infection through
the involvement of the transcription factor STAT1. But, the contribution of interferon to immune homeostasis
in the absence of acute infection remains unexplored. The authors report that STAT1KO mice develop spontaneous tumors characterized
by bone marrow hyperplasia and splenic accumulation of hematopoietic stem cells. Besides, intestinal tumors developed in these animals. Analysis of intestinal bacteria revealed severe dysbiosis in the absence of strong IFN signaling. leading to the expansion of TH17 cells and loss of splenic Trig cells. Reducing bacterial load by antibiotic treatment prevents TH17 bias, and blockade of IL17 signaling prevents it. medullary expansion and splenic stem cell accumulation. Thus, potent interferons modulate the intestinal microbial.
ecology necessary to maintain physiological immune homeostasis and prevent inflammation.
Interferon (IFN) is an important mediator of innate and adaptive immunity. Interferons generally consist of three types of cytokines: the type I interferon family, coded by different genes. especially different types of interferon-α and interferon-β; Interferon type II family. which is the only member of interferon-γ; The type III interferon family consists of several interferon-λs and each interferon
family signals through a different heterodimeric cell surface receptor.
All members of interferon-I, two members of the signal transducer and activator. which leads to the activation of JAK1 and Tyk2 JAK kinases. STAT1 and STAT2 are activated and interferon regulatory factor (IRF) 9 forms ISGF3, a heterotrimeric complex that binds. interferon-stimulated response elements in the promoters of hundreds of interferon-stimulated genes. This signaling cascade consists of the IFN-III subunits IL28Rα and IL10Rb and activates ISGF3. when it interacts with the IFN-I downstream pathway. In contrast, IFN-II signals through the STAT1 ligand after binding to the cognate receptor (IFNGR)
And stimulating a set of genes including the gamma activator sequence (GAS). All these pathways target STAT1, and STAT1 deficiency or hypofunction results in insensitivity
To all interferons. As expected, STAT1-deficient humans are susceptible to viral and mycobacterial infections
And hematopoietic stem cell transplantation remains the only curative option.
STAT1-deficient patients fail to thrive in the absence of anti-microbial innate immunity.
which hampers the study of STAT1's contribution to homeostasis. But, patients with partial loss of STAT1 function (LOF) have chronic colitis as well as severe infections. But, individuals with gain-of-function (GOF) STAT1 mutations often suffer from mucosal diseases because TH17 cell levels are reduced, thereby affecting the important regulatory function of STAT1.
Although involved in the same downstream signaling cascade, it appears. that interferon-I and -III play different roles in innate immunity to microbes.
and take part in different ways in the overall immune function of the host. For example, interferon-III has been shown to reduce inflammation by reducing
the number of IL-17-producing T helper TH17 cells and limiting neutrophil recruitment. , besides its important role in inflammation, IL-17 also plays an important role in hematopoiesis. For example, IL-17 stimulates myeloid and erythroid lineages, suggesting that IFN-III may play a role in hematopoietic regulation by limiting IL-17 activity. In addition, due to the more limited distribution of their receptors, members of IFN-III show an increased capacity to fight the invasion of pathogens in the mucosal site, inhibit hyperinflammation, and help maintain the integrity of the barrier.
Accumulating evidence shows that the general intestinal microflora in the mucosa also plays an important role in the formation of immunity. However, understanding the importance of microbial IFN interactions in preventing pathogenesis is limited. Here, the authors reveal the role of STAT1 in controlling microbial ecology that prevents inflammation and maintains immune homeostasis in the absence of infectious challenges. Research shows that the IFN pathway mediates tetanic signaling through actin
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