A recent study from the Mhlanga lab published in Nature Genetics, “A chromatin-regulated biphasic circuit coordinates IL-1β-mediated inflammation” sheds light on an intriguing locus harboring the proinflammatory cytokine IL1b and the anti inflammatory cytokine IL37. Their study focuses on a region between these two genes that harbors SNPs associated with altered immune responses in individuals during infection. They show that this region encodes the long noncoding RNA they name AMANZI (A MAster Noncoding RNA antagoniZing Inflammation) where the common variant RS16944 resides. IL1, AMANZI and IL37 all lie within a topologically associating domain and if an individual is AA at the locus they show increased risk for lethal sepsis as they have higher expression and more stable AMANZI transcript promoting IL37 while inhibiting IL1b. They highlight the importance of AMANZI as a negative regulator during b-glucan driven trained immunity. This work is highly impactful showcasing how SNPs in noncoding regions can have big impacts on the balance of the immune response.
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A chromatin-regulated biphasic circuit coordinates IL-1β-mediated inflammation
PMID: 38092881 DOI: 10.1038/s41588-023-01598-2
Abstract
Inflammation is characterized by a biphasic cycle consisting initially of a proinflammatory phase that is subsequently resolved by anti-inflammatory processes. Interleukin-1β (IL-1β) is a master regulator of proinflammation and is encoded within the same topologically associating domain (TAD) as IL-37, which is an anti-inflammatory cytokine that opposes the function of IL-1β. Within this TAD, we identified a long noncoding RNA called AMANZI, which negatively regulates IL-1β expression and trained immunity through the induction of IL37 transcription. We found that the activation of IL37 occurs through the formation of a dynamic long-range chromatin contact that leads to the temporal delay of anti-inflammatory responses. The common variant rs16944 present in AMANZI augments this regulatory circuit, predisposing individuals to enhanced proinflammation or immunosuppression. Our work illuminates a chromatin-mediated biphasic circuit coordinating expression of IL-1β and IL-37, thereby regulating two functionally opposed states of inflammation from within a single TAD.
© 2023. The Author(s), under exclusive licence to Springer Nature America, Inc.
