Maladaptive Trained Immunity: New Insight into the Pathogenesis of Inflammatory Bowel Disease

Abstract

Inflammatory bowel disease (IBD), including ulcerative colitis (UC) and Crohn’s disease (CD), is increasing globally and in Canada. IBD causes debilitating symptoms and significant economic strain on healthcare systems. Despite treatment advances, no universally effective therapy exists. Chronic uncontrolled inflammation of the intestinal mucosa remains the hallmark of the disease. A dysregulated immune response, particularly involving innate immune cells like macrophages, plays a central role in the pathogenesis of IBD. However, the mechanisms driving inflammatory macrophage activation are poorly understood. Recent studies suggest that innate immune cells, such as macrophages, can develop "immunologic memory" after exposure to microbes or pathogen signals. This memory, termed trained immunity (TI), boosts the immune response to future threats. While TI is protective against infections, it may worsen and drive disease progression in chronic inflammation disorders like IBD. To address this knowledge gap, we investigated the role of the bone marrow (BM) hematopoietic stem cells (HSC) and progenitors as a source of trained inflammatory and damage-inducing macrophages in an experimental model of acute colitis. Chemical-induced colitis models showed an expansion of HSCs in the BM and their biasedness towards myelopoiesis, as evidenced by increased granulocyte-macrophage precursors (GMPs). Further, macrophages derived from these altered BM precursors (BMDMs) displayed a pro-inflammatory phenotype at the baseline, without ex vivo stimulation, compared to BMDMs from untreated mice. After a four-week rest period to allow inflammation to return to baseline, we found that BMDMs from rested mice were significantly more pro-inflammatory, as evidenced by increased IL-6, IL-1b, and TNF-a secretion and enhanced glycolytic metabolism. In vivo, these rested mice exhibited heightened inflammation upon secondary challenge with DSS or lipopolysaccharide (LPS). Additionally, chimeric mouse experiments revealed that the trained immune phenotype persisted in the BM compartment for up to 14 weeks post-initial DSS exposure. Our findings suggest that TI within the BM is a critical factor in the development and persistence within a model of colitis and, therefore, may be relevant to inflammation in IBD. This study provides new insight into the role of HSCs in IBD pathogenesis and highlights the BM as a potential target for future therapeutic intervention.