Chronic inflammation represents a major threat to human health since long-term systemic inflammation is known to affect distinct tissues and organs. Recently, solid evidence demonstrated that chronic inflammation affects hematopoiesis; however, how chronic inflammation affects hematopoietic stem cells (HSCs) on the mechanistic level is poorly understood. Here, we employ a mouse model of chronic multifocal osteomyelitis (CMO) to assess the effects of a spontaneously developed inflammatory condition on HSCs. We demonstrate that hematopoietic and nonhematopoietic compartments in CMO BM contribute to HSC expansion and impair their function. Remarkably, our results suggest that the typical features of murine multifocal osteomyelitis and the HSC phenotype are mechanistically decoupled. We show that the CMO environment imprints a myeloid gene signature and imposes a pro-inflammatory profile on HSCs. We identify IL-6 and the Jak/Stat3 signaling pathway as critical mediators. However, while IL-6 and Stat3 blockage reduce HSC numbers in CMO mice, only inhibition of Stat3 activity significantly rescues their fitness. Our data emphasize the detrimental effects of chronic inflammation on stem cell function, opening new venues for treatment.

Childhood Leukaemia Investigation Prague Department of Pediatric Haematology and Oncology 2nd Faculty of Medicine Charles University Prague University Hospital Motol Prague Czech Republic

Department of Hemato Oncology Institute of Molecular Genetics of the Czech Academy of Sciences Prague Czech Republic

Department of Immunological and Tumor models Institute of Molecular Genetics of the Czech Academy of Sciences Prague Czech Republic

Department of Leukocyte signaling Institute of Molecular Genetics of the Czech Academy of Sciences Prague Czech Republic

Faculty of Science Charles University Prague Czech Republic

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WBP1L regulates hematopoietic stem cell function and T cell development