ERK1/2 activation in anti-inflammatory effects and underlying signaling mechanisms.

INTRODUCTION

ERK1/2 are core components of the MAPK signaling pathway and play a central role in the regulation of inflammation. Although ERK1/2 activation is well established for driving pro-inflammatory responses, accumulating evidence systematically summarized in this review demonstrates that ERK1/2 activation can also exert potent anti-inflammatory and pro-resolving effects. At the cellular level, ERK1/2 activation mediates anti-inflammatory regulation through multiple coordinated mechanisms: It promotes activation-induced cell death in T cells, drives macrophages and microglia toward anti-inflammatory phenotypes while fine-tuning their phagocytic activity, enhances efferocytosis of apoptotic cells by myeloid cells to drive inflammation resolution, inhibits dendritic cell maturation, and induces production of the key anti-inflammatory cytokine IL-10. At the molecular signaling pathway level, ERK1/2 suppresses pro-inflammatory NF-κB activity by stabilizing IκBα, directly interacting with NF-κB p65 subunit, or activating PPARγ in both immune cells and tissue-resident cells. In addition, ERK1/2 exerts anti-inflammatory effects through the Nrf2/HO-1 axis, which negatively regulates NF-κB. Further anti-inflammatory axes include the ERK1/2/CREB pathway and the FPR2/ERK1/2 pro-resolving signaling cascade. Other anti-inflammatory mechanisms include the ERK1/2/sCD14 axis that neutralizes LPS, ERK1/2-induced autophagy, and anti-inflammatory signaling triggered by diverse upstream regulators of ERK1/2.

CONCLUSION

This review systematically consolidates the anti-inflammatory and pro-resolving effects of ERK1/2 activation and the underlying molecular mechanisms involved. These findings provide robust evidence that ERK1/2 activation can promote anti-inflammatory and inflammation-resolving responses and refine our understanding of the dual role of ERK1/2 as a "double-edged sword" in the regulation of inflammation.