IL-1β signaling as a molecular arbiter of stem cell plasticity: orchestrating the niches of repair, fibrosis, and cancer

Abstract

Interleukin-1(3 (IL-1(3) has long been characterized as a foundational mediator of innate immunity, yet this designation captures only a fraction of its biological significance. A growing body of evidence now positions IL-1(3 as a molecular arbiter of tissue restoration - a context-sensitive instructor that orchestrates the dynamic interplay between inflammatory signaling, stem cell fate, and niche remodeling that collectively determines whether an injured tissue regenerates or degenerates. Far beyond its canonical role in host defense, IL-1(3 functions as a critical regulator of cell state plasticity, driving the transition of lineage-committed progenitors into highly plastic, transitional identities that are indispensable for effective wound repair. Yet the very mechanisms that render IL-1(3 essential for regeneration also render it capable of profound pathological consequence when its activity is sustained, amplified, or spatiotemporally dysregulated. This review explores the spatiotemporal logic governing IL-1(3-mediated plasticity, with particular emphasis on the respiratory epithelium as a primary and instructive model of inflammatory reprogramming and niche remodeling. We examine how the signaling thresholds, cellular contexts, and temporal dynamics of IL-1(3 activity collectively determine regenerative outcomes - and how the failure to terminate this program pathologically stabilizes transitional progenitor states, predisposing tissues to fibrosis, functional exhaustion, and malignant transformation. By integrating evidence spanning transcriptional, epigenetic, and metabolic rewiring, we propose a unified conceptual framework for understanding IL-1(3 as a master coordinator of the regenerative ecosystem - one whose precise modulation represents a compelling therapeutic target for resetting pathological cell states toward functional recovery in chronic inflammatory diseases.