Nuclear IL-33-driven UBE4B expression tilts human macrophages toward the M2 phenotype via p53 ubiquitination

Interleukin-33 (IL-33), a member of the IL-1 cytokine family, has emerged as a chromatin-associated cytokine with the potential to modulate gene expression through chromatin remodeling and epigenetic regulation. Despite its established role in immune responses, the specific genes regulated by nuclear IL-33 and its mechanisms remain elusive. Our research has found that overexpression of full-length IL-33 in human monocytes promotes the expression of the ubiquitin ligase UBE4B, leading to the ubiquitination and degradation of p53. Thence, our study indicates that full-length IL-33 can significantly inhibit the tumor suppressor p53, which may be the main reason for IL-33's impact on the macrophage polarization. Therefore, this study uncovers new functions of IL-33 in the nucleus and its role in macrophage behavior through p53 regulation. This insight could guide the development of targeted therapeutics for disorders involving macrophage dysregulation.