01
Interferon-gamma (IFN-γ) is a critical cytokine in the immune response to viral and intracellular bacterial infections in mammals. The expression of IFN-γ is tightly regulated due to its role in host defense, autoimmune responses, tumor surveillance, and neuronal function. While several enhancers have been identified to promote IFN-γ responses, there has been a lack of understanding regarding the silencers that control the Ifng gene. This study aimed to fill this gap by investigating the regulatory elements that restrain IFN-γ expression, which is crucial for maintaining tissue homeostasis and preventing autoimmunity.
The researchers identified a distal silencer, CNS–28, within the Ifng locus that represses Ifng expression. They found that CNS–28 maintains Ifng silence by reducing enhancer-promoter interactions within the Ifng locus in a GATA3-dependent but T-bet-independent manner. The study functionally demonstrated that CNS–28 restrains Ifng transcription in NK cells, CD4+, and CD8+ T cells during both innate and adaptive immune responses. Furthermore, the deficiency of CNS–28 resulted in repressed type 2 responses due to elevated IFN-γ expression, indicating a shift in the Th1 and Th2 paradigm. The study employed various experimental approaches, including genetic deletion of Mll4, H3K4me1 binding profile analysis, and the generation of mice lacking CNS–28, to elucidate the role of this silencer in immune cell quiescence and autoimmunity.
The study concluded that CNS–28 is a critical negative regulatory element that ensures immune cell quiescence by cooperating with other regulatory cis elements within the Ifng gene locus to minimize autoimmunity. The deletion of CNS–28 led to enhanced IFN-γ production and tissue inflammation, highlighting the importance of this silencer in regulating immune responses. The findings provide insights into the mechanisms of IFN-γ gene regulation and suggest that targeting the Ifng silencer CNS–28 could have therapeutic potential in conditions involving dysregulated IFN-γ expression.
DOI: 10.1016/j.immuni.2023.03.006
02
Numerous studies have demonstrated that individuals with enteritis frequently experience extra-intestinal organ complications, particularly in the realms of peripheral coagulation dysfunction and thrombosis. As a hormone predominantly produced in the gut, 5-HT is capable of being absorbed and stored by peripheral platelets, which subsequently impacts the body's coagulation mechanisms.
This study revealed that in a murine model of enteritis, there is a simultaneous increase in peripheral coagulation, thereby heightening the risk of thrombosis. Further experimentation indicated that the destruction of epithelial cells due to intestinal inflammation promotes the release of IL-33 from these cells, elevating peripheral serum levels of 5-HT and thus stimulating platelet activation and coagulation. Concurrently, the peripheral administration of IL-33 can rapidly elevate 5-HT levels, further enhancing coagulation capabilities. Additionally, they elucidated that the release of 5-HT and platelet activation triggered by intestinal IL-33 can influence peripheral wound healing through the recruitment of neutrophils. In a similar vein, intestinal IL-33 and 5-HT can modulate the progression of systemic acute sepsis by affecting neutrophils. By employing various 5-HT receptor antagonists, supplementing peripheral 5-HT precursors or IL-33 protein, and neutralizing peripheral IL-33, they were able to modulate the migration and recruitment of neutrophils during acute inflammation to varying extents, ultimately impacting the course of inflammation.
This study underscores the significant role of the interplay between the intestinal immune and endocrine systems in directly regulating platelet function, which is crucial for intervening in systemic physiological and pathological processes as well as the initiation and progression of inflammation. Most notably, this research not only delineates the regulatory mechanisms of peripheral coagulation by intestinal inflammation but also provides further validation and exploration of the intestinal IL-33-5-HT signaling pathway as a potential therapeutic target.
DOI: 10.1182/blood.2021013474
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Editor & Reviewer: Yanwen Zhu
