Reciprocal suppression between TGFβ signaling and TNF stimulation finetunes the macrophage inflammatory response.
Academic Article
Overview
abstract
Inflammation plays a crucial role in the development of various disease conditions or is closely associated with them. Inflammatory cytokines like TNF often engage in interactions with other cytokines and growth factors, including TGFβ, to orchestrate inflammatory process. Basal/endogenous TGFβ signaling is a universal presence, yet the precise way TNF communicates with TGFβ signaling to regulate inflammation and influence inflammatory levels in macrophages has remained elusive. To address this question, this study utilized genetic approaches and a combination of molecular and cellular methods, including conditional TGFβ receptor knockout mice, human cells, RNAseq, ATACseq and Cut & Run-seq. The results reveal that the TGFβ signaling functions as a vital homeostatic pathway, curtailing uncontrolled inflammation in macrophages in response to TNF. Conversely, TNF employs two previously unrecognized mechanisms to suppress the TGFβ signaling. These mechanisms encompass epigenetic inhibition and RBP-J-mediated inhibition of the TGFβ signaling pathway by TNF. These mechanisms empower TNF to diminish the antagonistic influence exerted by the TGFβ signaling pathway, ultimately enhancing TNF's capacity to induce heightened levels of inflammation. This reciprocal suppression dynamic between TNF and the TGFβ signaling pathway holds unique physiopathological significance, as it serves as a crucial "braking" mechanism. The balance between TNF levels and the activity of the endogenous TGFβ signaling pathway plays a pivotal role in determining the overall extent of inflammation. The potential for therapeutically augmenting the TGFβ signaling pathway presents an intriguing avenue for countering the impact of TNF and, consequently, developing innovative strategies for inflammation control.
