Interleukin-33 in the Regulation of Autophagy and Apoptosis in Macrophages During Infection.

Interleukin-33 (IL-33) is a multifunctional cytokine from the interleukin-1 family that plays a pivotal role in modulating macrophage responses during infection. Functioning both as an extracellular alarmin and as a nuclear transcriptional regulator, IL-33 orchestrates a dynamic balance between autophagy and apoptosis, crucial for immune homeostasis. A systematic literature search was conducted in PubMed, Web of Science, and Scopus for studies published between January 2010 and April 2025. Search terms combined "Interleukin-33" with keywords related to autophagy, apoptosis, macrophages, and infection. It enhances autophagy by activating AMP-activated protein kinase (AMPK), inhibiting mechanistic target of rapamycin (mTOR), and interacting with Beclin-1 to promote autophagosome formation and LC3 lipidation. Concurrently, IL-33 suppresses apoptosis by upregulating Bcl-2 and Mcl-1, inhibiting Bax/Bak-mediated mitochondrial outer membrane permeabilization (MOMP), and blocking caspase activation. Recent studies also highlight the importance of post-translational modifications (PTMs) and the nuclear domain of IL-33 in fine-tuning these responses. Furthermore, IL-33-based combination therapies with immune checkpoint inhibitors (ICIs) are emerging as promising immunotherapeutic strategies. This review synthesizes current insights into IL-33-mediated regulation of macrophage fate and identifies key research gaps. A better understanding of the context-dependent roles of IL-33 will be critical for translating these mechanisms into effective, targeted therapies for infectious and inflammatory diseases.