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.

• Keywords
• IL-6/Jak/Stat3, chronic inflammation, chronic multifocal osteomyelitis, hematopoietic stem cells, niche,
• MeSH
• Hematopoietic Stem Cells metabolism   MeSH
• Hematopoiesis MeSH
• Interleukin-6 * genetics   metabolism   MeSH
• Humans MeSH
• Mice MeSH
• Osteomyelitis MeSH
• Signal Transduction MeSH
• STAT3 Transcription Factor genetics   metabolism   MeSH
• Inflammation * metabolism   MeSH
• Animals MeSH
• Check Tag
• Humans MeSH
• Mice MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Names of Substances
• Interleukin-6 * MeSH
• STAT3 protein, human MeSH Browser
• STAT3 Transcription Factor MeSH

INTRODUCTION: Autoinflammatory diseases are characterized by dysregulation of innate immune system leading to spontaneous sterile inflammation. One of the well-established animal models of this group of disorders is the mouse strain Pstpip2cmo . In this strain, the loss of adaptor protein PSTPIP2 leads to the autoinflammatory disease chronic multifocal osteomyelitis. It is manifested by sterile inflammation of the bones and surrounding soft tissues of the hind limbs and tail. The disease development is propelled by elevated production of IL-1β and reactive oxygen species by neutrophil granulocytes. However, the molecular mechanisms linking PSTPIP2 and these pathways have not been established. Candidate proteins potentially involved in these mechanisms include PSTPIP2 binding partners, PEST family phosphatases (PEST-PTPs) and phosphoinositide phosphatase SHIP1. METHODS: To address the role of these proteins in PSTPIP2-mediated control of inflammation, we have generated mouse strains in which PEST-PTP or SHIP1 binding sites in PSTPIP2 have been disrupted. In these mouse strains, we followed disease symptoms and various inflammation markers. RESULTS: Our data show that mutation of the PEST-PTP binding site causes symptomatic disease, whereas mice lacking the SHIP1 interaction site remain asymptomatic. Importantly, both binding partners of PSTPIP2 contribute equally to the control of IL-1β production, while PEST-PTPs have a dominant role in the regulation of reactive oxygen species. In addition, the interaction of PEST-PTPs with PSTPIP2 regulates the production of the chemokine CXCL2 by neutrophils. Its secretion likely creates a positive feedback loop that drives neutrophil recruitment to the affected tissues. CONCLUSIONS: We demonstrate that PSTPIP2-bound PEST-PTPs and SHIP1 together control the IL-1β pathway. In addition, PEST-PTPs have unique roles in the control of reactive oxygen species and chemokine production, which in the absence of PEST-PTP binding to PSTPIP2 shift the balance towards symptomatic disease.

• Keywords
• PEST-family phosphatases, PSTPIP2, SHIP1, autoinflammation, chronic multifocal osteomyelitis, neutrophils,
• MeSH
• Adaptor Proteins, Signal Transducing * metabolism   MeSH
• Cytoskeletal Proteins * metabolism   MeSH
• Mice MeSH
• Neutrophils * MeSH
• Osteomyelitis MeSH
• Reactive Oxygen Species metabolism   MeSH
• Inflammation MeSH
• Animals MeSH
• Check Tag
• Mice MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Names of Substances
• Adaptor Proteins, Signal Transducing * MeSH
• Cytoskeletal Proteins * MeSH
• Pstpip2 protein, mouse MeSH Browser
• Reactive Oxygen Species MeSH

A number of human autoinflammatory diseases manifest with severe inflammatory bone destruction. Mouse models of these diseases represent valuable tools that help us to understand molecular mechanisms triggering this bone autoinflammation. The Pstpip2cmo mouse strain is among the best characterized of these; it harbors a mutation resulting in the loss of adaptor protein PSTPIP2 and development of autoinflammatory osteomyelitis. In Pstpip2cmo mice, overproduction of interleukin-1β (IL-1β) and reactive oxygen species by neutrophil granulocytes leads to spontaneous inflammation of the bones and surrounding soft tissues. However, the upstream signaling events leading to this overproduction are poorly characterized. Here, we show that Pstpip2cmo mice deficient in major regulator of Src-family kinases (SFKs) receptor-type protein tyrosine phosphatase CD45 display delayed onset and lower severity of the disease, while the development of autoinflammation is not affected by deficiencies in Toll-like receptor signaling. Our data also show deregulation of pro-IL-1β production by Pstpip2cmo neutrophils that are attenuated by CD45 deficiency. These data suggest a role for SFKs in autoinflammation. Together with previously published work on the involvement of protein tyrosine kinase spleen tyrosine kinase, they point to the role of receptors containing immunoreceptor tyrosine-based activation motifs, which after phosphorylation by SFKs recruit spleen tyrosine kinase for further signal propagation. We propose that this class of receptors triggers the events resulting in increased pro-IL-1β synthesis and disease initiation and/or progression.

• Keywords
• CD45, PSTPIP2, PTPRC, autoinflammation, chronic recurrent multifocal osteomyelitis,
• MeSH
• Adaptor Proteins, Signal Transducing genetics   immunology   MeSH
• Leukocyte Common Antigens genetics   immunology   MeSH
• Cytoskeletal Proteins genetics   immunology   MeSH
• Diabetes Mellitus, Type 1 genetics   immunology   pathology   MeSH
• Interleukin-1beta genetics   immunology   MeSH
• Mice, Knockout MeSH
• Mice MeSH
• Neutrophils immunology   pathology   MeSH
• Osteomyelitis genetics   immunology   pathology   MeSH
• Signal Transduction genetics   immunology   MeSH
• Severity of Illness Index MeSH
• Toll-Like Receptors genetics   immunology   MeSH
• Animals MeSH
• Check Tag
• Mice MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Names of Substances
• Adaptor Proteins, Signal Transducing MeSH
• Leukocyte Common Antigens MeSH
• Cytoskeletal Proteins MeSH
• IL1B protein, mouse MeSH Browser
• Interleukin-1beta MeSH
• Pstpip2 protein, mouse MeSH Browser
• Ptprc protein, mouse MeSH Browser
• Toll-Like Receptors MeSH