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.
- MeSH
- hematopoetické kmenové buňky metabolismus MeSH
- hematopoéza MeSH
- interleukin-6 * genetika metabolismus MeSH
- lidé MeSH
- myši MeSH
- signální transdukce MeSH
- transkripční faktor STAT3 genetika metabolismus MeSH
- zánět * metabolismus MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- myši MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
An advantageous alternative to the use of detergents in biochemical studies on membrane proteins are the recently developed styrene-maleic acid (SMA) amphipathic copolymers. In our recent study [1] we demonstrated that using this approach, most T cell membrane proteins were fully solubilized (presumably in small nanodiscs), while two types of raft proteins, GPI-anchored proteins and Src family kinases, were mostly present in much larger (>250 nm) membrane fragments markedly enriched in typical raft lipids, cholesterol and lipids containing saturated fatty acid residues. In the present study we demonstrate that disintegration of membranes of several other cell types by means of SMA copolymer follows a similar pattern and we provide a detailed proteomic and lipidomic characterization of these SMA-resistant membrane fragments (SRMs).
OBJECTIVES: The main objective of this study was to determine whether infrared thermography could be used as an efficient technique to evaluate the impact of a birth-related brachial plexus injury on the temperature of the injured arm and whether it could be used as a complementary method when diagnosing this injury in clinical praxis. BACKGROUND: Clinically, the brachial plexus injury is a peripheral paresis, which occurs when nerves that send signals from the spinal cord to the shoulder, arm, and hand are stretched or compressed. In principle, the brachial plexus injury, as a long-lasting injury, should be causing hypothermia of the injured arm. METHODS: The usage of contactless infrared thermography could offer a “new view” of the diagnostic process in this case. The present study, therefore, describes a process of clinical infrared thermography examination of three patients of different age and presents results from those examinations. RESULTS AND CONCLUSION: From our results, it can be confirmed that the birth-related brachial plexus injury affects the temperature of the affected arm, especially in the area of the cubital fossa, to an extent that the thermal camera is capable of detecting significant temperature differences between the healthy and injured arms (Tab. 3, Fig. 7, Ref. 13).
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.
- MeSH
- adaptorové proteiny signální transdukční * metabolismus MeSH
- cytoskeletální proteiny * metabolismus MeSH
- myši MeSH
- neutrofily * MeSH
- reaktivní formy kyslíku metabolismus MeSH
- zánět MeSH
- zvířata MeSH
- Check Tag
- myši MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- Publikační typ
- abstrakt z konference 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.
- MeSH
- adaptorové proteiny signální transdukční genetika imunologie MeSH
- antigeny CD45 genetika imunologie MeSH
- cytoskeletální proteiny genetika imunologie MeSH
- diabetes mellitus 1. typu genetika imunologie patologie MeSH
- interleukin-1beta genetika imunologie MeSH
- myši knockoutované MeSH
- myši MeSH
- neutrofily imunologie patologie MeSH
- osteomyelitida genetika imunologie patologie MeSH
- signální transdukce genetika imunologie MeSH
- stupeň závažnosti nemoci MeSH
- toll-like receptory genetika imunologie MeSH
- zvířata MeSH
- Check Tag
- myši MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
LST1 is a small adaptor protein expressed in leukocytes of myeloid lineage. Due to the binding to protein tyrosine phosphatases SHP1 and SHP2 it was thought to have negative regulatory function in leukocyte signaling. It was also shown to be involved in cytoskeleton regulation and generation of tunneling nanotubes. LST1 gene is located in MHCIII locus close to many immunologically relevant genes. In addition, its expression increases under inflammatory conditions such as viral infection, rheumatoid arthritis and inflammatory bowel disease and its deficiency was shown to result in slightly increased sensitivity to influenza infection in mice. However, little else is known about its role in the immune system homeostasis and immune response. Here we show that similar to humans, LST1 is expressed in mice in the cells of the myeloid lineage. In vivo, its deficiency results in alterations in multiple leukocyte subset abundance in steady state and under inflammatory conditions. Moreover, LST1-deficient mice show significant level of resistance to dextran sodium sulphate (DSS) induced acute colitis, a model of inflammatory bowel disease. These data demonstrate that LST1 regulates leukocyte abundance in lymphoid organs and inflammatory response in the gut.
- MeSH
- biologické markery MeSH
- dendritické buňky imunologie metabolismus MeSH
- fosforylace MeSH
- genotyp MeSH
- intracelulární signální peptidy a proteiny genetika metabolismus MeSH
- kolitida etiologie metabolismus patologie MeSH
- leukocyty imunologie metabolismus MeSH
- lidé MeSH
- lipopolysacharidy imunologie MeSH
- makrofágy imunologie metabolismus MeSH
- membránové proteiny genetika metabolismus MeSH
- modely nemocí na zvířatech MeSH
- myši knockoutované MeSH
- myši MeSH
- náchylnost k nemoci MeSH
- regulace genové exprese * MeSH
- signální transdukce * MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- myši MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
WW domain binding protein 1-like (WBP1L), also known as outcome predictor of acute leukaemia 1 (OPAL1), is a transmembrane adaptor protein, expression of which correlates with ETV6-RUNX1 (t(12;21)(p13;q22)) translocation and favourable prognosis in childhood leukaemia. It has a broad expression pattern in haematopoietic and in non-haematopoietic cells. However, its physiological function has been unknown. Here, we show that WBP1L negatively regulates signalling through a critical chemokine receptor CXCR4 in multiple leucocyte subsets and cell lines. We also show that WBP1L interacts with NEDD4-family ubiquitin ligases and regulates CXCR4 ubiquitination and expression. Moreover, analysis of Wbp1l-deficient mice revealed alterations in B cell development and enhanced efficiency of bone marrow cell transplantation. Collectively, our data show that WBP1L is a novel regulator of CXCR4 signalling and haematopoiesis.
- MeSH
- adaptorové proteiny signální transdukční metabolismus MeSH
- glykoproteiny metabolismus MeSH
- HEK293 buňky MeSH
- hematopoetické kmenové buňky metabolismus MeSH
- hematopoéza * MeSH
- homeostáza MeSH
- lidé MeSH
- lipoylace MeSH
- malá interferující RNA metabolismus MeSH
- membránové proteiny genetika metabolismus MeSH
- myši inbrední C57BL MeSH
- receptory CXCR4 metabolismus MeSH
- signální transdukce * MeSH
- ubikvitinace MeSH
- ubikvitinligasy metabolismus MeSH
- vazba proteinů MeSH
- zárodečné buňky metabolismus MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
Main symptoms found in patients with same diseases as for example COVID-19 is febrile. The infrared thermography (IRT) represents a fast measurement in case of screening in public places. One of the limitations of IRT is the resolution of sensor, which has close connection with the distance between camera and ROI. To maximize the effectivity of resolution of the camera is to reduce the distance from the object. The aim of presented study showed the possibility how to protect the camera or medical staff that operates the device against potential infection or contamination from the person with infection. Two protective foils of different thickness (40 μm; 9 μm) were tested as a barrier between the IRT and the ROI (black body model and human face). Even though the results have shown that the transparent foils decrease linearly the measured value of the temperature, it can be used as a protective barrier between IRT and the object if an appropriate recalculation is done during analysis of IRT images. Results are acceptable in the case of 9μm foil especially. The authors see this possibility as a minor concession from IRT standards but as a great help in health protection. The transparent foil can be used as protective barrier of the infrared camera.
- MeSH
- COVID-19 prevence a kontrola MeSH
- horečka diagnóza MeSH
- infračervené záření MeSH
- kůže diagnostické zobrazování MeSH
- lidé MeSH
- tělesná teplota * MeSH
- termografie * metody MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- práce podpořená grantem MeSH
Autoinflammatory diseases are characterized by dysregulation of the innate immune system, leading to spontaneous inflammation. Pstpip2cmo mouse strain is a well-characterized model of this class of disorders. Because of the mutation leading to the lack of adaptor protein PSTPIP2, these animals suffer from autoinflammatory chronic multifocal osteomyelitis similar to several human syndromes. Current evidence suggests that it is driven by hyperproduction of IL-1β by neutrophil granulocytes. In this study, we show that in addition to IL-1β, PSTPIP2 also negatively regulates pathways governing reactive oxygen species generation by neutrophil NOX2 NADPH oxidase. Pstpip2cmo neutrophils display highly elevated superoxide production in response to a range of stimuli. Inactivation of NOX2 NADPH oxidase in Pstpip2cmo mice did not affect IL-1β levels, and the autoinflammatory process was initiated with similar kinetics. However, the bone destruction was almost completely alleviated, suggesting that dysregulated NADPH oxidase activity is a key factor promoting autoinflammatory bone damage in Pstpip2cmo mice.
- MeSH
- adaptorové proteiny signální transdukční genetika metabolismus MeSH
- buněčné linie MeSH
- cytoskeletální proteiny genetika metabolismus MeSH
- interleukin-1beta imunologie metabolismus MeSH
- kosti a kostní tkáň imunologie patologie MeSH
- lidé MeSH
- modely nemocí na zvířatech MeSH
- mutace MeSH
- myši transgenní MeSH
- myši MeSH
- NADPH-oxidasa 2 genetika metabolismus MeSH
- neutrofily imunologie metabolismus MeSH
- osteomyelitida genetika imunologie patologie MeSH
- primární buněčná kultura MeSH
- signální transdukce genetika imunologie MeSH
- superoxidy imunologie metabolismus MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- myši MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
