Inflammatory hematopoiesis drives intestinal inflammation and is modulated by anti-TNF therapy 2309660

Abstract Introduction Chronic inflammatory diseases often originate in local tissues yet display systemic immune abnormalities, suggesting durable changes in upstream immune regulation. Crohn’s disease (CD), while centered in the intestine, is a systemic inflammatory disorder. Hematopoietic stem and progenitor cells (HSPCs) can retain memory of inflammatory cues, leading to sustained changes in hematopoiesis and immune responsiveness. Here, we investigated how chronic intestinal inflammation in CD reprograms HSPCs and contributes to disease. Methods We analyzed a longitudinal CD cohort using paired pre- and post—anti-TNF blood samples with healthy controls. Circulating HSPCs and mature immune cells were profiled by single-nucleus RNA-seq and ATAC-seq with progenitor enrichment, enabling integrated multiomic and gene regulatory analyses. Functional relevance was assessed using bulk RNA-seq and ATAC-seq of HSPCs from a murine DSS colitis model, together with bone marrow chimera and transplantation experiments. Results HSPCs from individuals with CD exhibited loss of quiescence, metabolic activation, epigenetic priming of inflammatory and stress-responsive programs, and shifts in progenitor composition. These molecular programs were conserved in murine colitis HSPCs, with altered progenitor subtype frequencies and pathogenic hematopoiesis, as inflammation-experienced HSPCs exacerbated disease upon transplantation. Circulating monocytes in CD also shifted toward inflammatory subpopulations sharing transcriptional and regulatory features with reprogrammed HSPCs. A central TNF—NF-κB regulatory axis underpinned these alterations, and anti-TNF therapy largely normalized HSPC composition, metabolic state, and inflammatory gene regulatory networks. Conclusion Inflammatory hematopoiesis represents a durable, therapy-responsive driver of CD. HSPCs act as a systemic reservoir of inflammatory memory, while TNF blockade partially restores hematopoietic homeostasis, highlighting progenitor reprogramming as a therapeutic target. Funding Source NA Topic Categories Hematopoiesis and Immune System Development (HEM)