Conserved noncoding sequence-9 regulates NFATc1-mediated IL-10 expression in B cells to control inflammatory responses

Abstract

Interleukin-10 (IL-10) production by B cells plays a critical role in regulating inflammatory responses, yet the mechanisms controlling its expression remain poorly understood. We identified a conserved noncoding sequence (CNS-9) as an essential regulatory element for IL-10 expression in mouse B cells. Comprehensive genomic analyses revealed that CNS-9 functions as an enhancer bound by the transcription factor NFATc1, which facilitates chromatin looping between CNS-9 and the IL-10 promoter to drive transcription. Flow cytometry analyses identified B1a cells as the predominant source of B cell-derived IL-10, with this production critically dependent on NFATc1-mediated CNS-9 regulation. In a mouse model of LPS-induced sepsis, deletion of CNS-9, B cell-specific NFATc1, or both resulted in reduced IL-10 production, exacerbated inflammatory responses, and decreased survival. Furthermore, we demonstrated that the human homolog, CNS-12, functions similarly through NFATc1-dependent mechanisms. These findings establish a conserved regulatory pathway controlling IL-10 expression in B cells with notable implications for inflammatory disease pathogenesis and potential therapeutic interventions.