A chromatin-regulated biphasic circuit coordinates IL-1β-mediated inflammation

Inflammation is characterized by a biphasic cycle consisting initially of a proinflammatory phase that is subsequently resolved by anti-inflammatory processes. Interleukin-1 beta (IL-1 beta) 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-1 beta. Within this TAD, we identified a long noncoding RNA called AMANZI, which negatively regulates IL-1 beta 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-1 beta and IL-37, thereby regulating two functionally opposed states of inflammation from within a single TAD. The long noncoding RNA AMANZI downregulates IL-1 beta expression and trained immunity by inducing IL-37 transcription via long-range chromatin contacts. The common variant rs16944 present in AMANZI modulates proinflammation or immunosuppression risk.

Automated summary

Inflammation is a biphasic cycle involving proinflammatory and anti-inflammatory processes. IL-1 beta and IL-37 are two cytokines encoded within the same topologically associating domain (TAD) and their expression is regulated by a long noncoding RNA called AMANZI. AMANZI downregulates IL-1 beta expression and trained immunity by inducing IL-37 transcription via long-range chromatin contacts.