Macrophage-driven inflammation in inflammatory bowel disease: mechanisms and therapeutic opportunities

Gut inflammation can be triggered by multiple factors, including the loss of intestinal homeostasis and dysregulation of the innate immune system, which compromise the epithelial barrier and lead to tissue damage. Intestinal innate immunity protects the host from invading pathogens and limits microbial translocation while maintaining tolerance toward the commensal microbiota. Disruption of this balance is considered an important contributor to intestinal inflammation in inflammatory bowel diseases (IBD), encompassing ulcerative colitis (UC) and Crohn's disease (CD). While IBD pathogenesis encompasses genetic susceptibility, epigenomic dysregulation, and environmental factors, this mini-review focuses on innate immune and macrophage-driven mechanisms that integrate these upstream signals into chronic mucosal inflammation. In this context, macrophages are key innate immune cells that provide a rapid first line of defense against conserved microbial and danger signals and play a central role in initiating and sustaining inflammatory responses. In this mini-review, we describe how disruption of intestinal homeostasis triggers activation of the innate immune system, including the recruitment and activation of macrophages. Specifically, we examine the functional polarization of macrophages during inflammation and its impact on disease progression in UC and CD. We highlight the role of inflammasomes, central components of innate immune signaling, which mediate the release of pro-inflammatory cytokines and pyroptotic cell death, thereby exacerbating tissue damage and disrupting host-microbiota interactions. We also discuss trained immunity, a process through which macrophages undergo long-lasting changes following repeated inflammatory signals, which may enhance their responses to future stimuli and contribute to persistent inflammation and disease recurrence in IBD. Finally, we review therapeutic strategies targeting macrophages and innate immune pathways. Despite clinical advances, current therapies remain limited and fail to address the complex inflammatory networks underlying IBD. A deeper understanding of innate immune and inflammasome-related pathways will be relevant for the development of multitargeted therapeutic strategies in IBD.