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The knowledge about the contribution of the innate immune system to health and disease is expanding. However, to obtain reliable results, it is critical to select appropriate mouse models for in vivo studies. Data on genetic and phenotypic changes associated with different mouse strains can assist in this task. Such data can also facilitate our understanding of how specific polymorphisms and genetic alterations affect gene function, phenotypes, and disease outcomes. Extensive information is available on genetic changes in all major mouse strains. However, comparatively little is known about their impact on immune response and, in particular, on innate immunity. Here, we analyzed a mouse model of chronic multifocal osteomyelitis, an autoinflammatory disease driven exclusively by the innate immune system, which is caused by an inactivating mutation in the Pstpip2 gene. We investigated how the genetic background of BALB/c, C57BL/6J, and C57BL/6NCrl strains alters the molecular mechanisms controlling disease progression. While all mice developed the disease, symptoms were significantly milder in BALB/c and partially also in C57BL/6J when compared to C57BL/6NCrl. Disease severity correlated with the number of infiltrating neutrophils and monocytes and with the production of chemokines attracting these cells to the site of inflammation. It also correlated with increased expression of genes associated with autoinflammation, rheumatoid arthritis, neutrophil activation, and degranulation, resulting in altered neutrophil activation in vivo. Together, our data demonstrate striking effects of genetic background on multiple parameters of neutrophil function and activity influencing the onset and course of chronic multifocal osteomyelitis.
- MeSH
- adaptorové proteiny signální transdukční genetika MeSH
- aktivace neutrofilů genetika MeSH
- cytoskeletální proteiny MeSH
- genetické pozadí * MeSH
- modely nemocí na zvířatech MeSH
- myši inbrední BALB C MeSH
- myši inbrední C57BL MeSH
- myši MeSH
- neutrofily * imunologie patologie MeSH
- osteomyelitida * genetika imunologie patologie MeSH
- přirozená imunita genetika MeSH
- stupeň závažnosti nemoci MeSH
- zánět genetika patologie MeSH
- zvířata MeSH
- Check Tag
- myši MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
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
Neutrophilic inflammation is a hallmark of many monogenic autoinflammatory diseases; pathomechanisms that regulate extravasation of damaging immune cells into surrounding tissues are poorly understood. Here we identified three unrelated boys with perinatal-onset of neutrophilic cutaneous small vessel vasculitis and systemic inflammation. Two patients developed liver fibrosis in their first year of life. Next-generation sequencing identified two de novo truncating variants in the Src-family tyrosine kinase, LYN, p.Y508*, p.Q507* and a de novo missense variant, p.Y508F, that result in constitutive activation of Lyn kinase. Functional studies revealed increased expression of ICAM-1 on induced patient-derived endothelial cells (iECs) and of β2-integrins on patient neutrophils that increase neutrophil adhesion and vascular transendothelial migration (TEM). Treatment with TNF inhibition improved systemic inflammation; and liver fibrosis resolved on treatment with the Src kinase inhibitor dasatinib. Our findings reveal a critical role for Lyn kinase in modulating inflammatory signals, regulating microvascular permeability and neutrophil recruitment, and in promoting hepatic fibrosis.
Folicular T helper lymphocytes (Tfh) were recently identified as a novel, fundamentally important subpopulation of helper T cells. Tfh are the major cell type providing help to B lymphocytes in their terminal differentiation into plasma cells producing high-affinity antibodies. Thus, Tfh cells apparently play the role previously assigned to Th2 lymphocytes.
- MeSH
- antigeny * MeSH
- B-lymfocyty * fyziologie imunologie MeSH
- imunitní systém fyziologie MeSH
- lidé MeSH
- Th1 buňky MeSH
- Th2 buňky MeSH
- Check Tag
- lidé MeSH
Transmembrane adaptor proteins are membrane-anchored proteins consisting of a short extracellular part, a transmembrane domain, and a cytoplasmic part with various protein-protein interaction motifs but lacking any enzymatic activity. They participate in the regulation of various signaling pathways by recruiting other proteins to the proximity of cellular membranes where the signaling is often initiated and propagated. In this work, we show that LST1/A, an incompletely characterized protein encoded by MHCIII locus, is a palmitoylated transmembrane adaptor protein. It is expressed specifically in leukocytes of the myeloid lineage, where it localizes to the tetraspanin-enriched microdomains. In addition, it binds SHP-1 and SHP-2 phosphatases in a phosphotyrosine-dependent manner, facilitating their recruitment to the plasma membrane. These data suggest a role for LST1/A in negative regulation of signal propagation.
- MeSH
- buněčná membrána metabolismus MeSH
- HEK293 buňky MeSH
- HeLa buňky MeSH
- hlavní histokompatibilní komplex fyziologie MeSH
- Jurkat buňky MeSH
- lidé MeSH
- membránové proteiny chemie genetika metabolismus MeSH
- molekulární sekvence - údaje MeSH
- myeloidní buňky cytologie metabolismus MeSH
- plakiny metabolismus MeSH
- primární buněčná kultura MeSH
- pseudopodia metabolismus MeSH
- sekvence aminokyselin MeSH
- signální transdukce fyziologie MeSH
- terciární struktura proteinů fyziologie MeSH
- transport proteinů fyziologie MeSH
- tyrosinfosfatasa nereceptorového typu 11 metabolismus MeSH
- tyrosinfosfatasa nereceptorového typu 6 metabolismus MeSH
- U937 buňky MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
Formation of the immunological synapse between an antigen-presenting cell (APC) and a T cell leads to signal generation in both cells involved. In T cells, the lipid raft-associated transmembrane adaptor protein LAT plays a central role. Its phosphorylation is a crucial step in signal propagation, including the calcium response and mitogen-activated protein kinase activation, and largely depends on its association with the SLP76 adaptor protein. Here we report the discovery of a new palmitoylated transmembrane adaptor protein, termed SCIMP. SCIMP is expressed in B cells and other professional APCs and is localized in the immunological synapse due to its association with tetraspanin-enriched microdomains. In B cells, it is constitutively associated with Lyn kinase and becomes tyrosine phosphorylated after major histocompatibility complex type II (MHC-II) stimulation. When phosphorylated, SCIMP binds to the SLP65 adaptor protein and also to the inhibitory kinase Csk. While the association with SLP65 initiates the downstream signaling cascades, Csk binding functions as a negative regulatory loop. The results suggest that SCIMP is involved in signal transduction after MHC-II stimulation and therefore serves as a regulator of antigen presentation and other APC functions.
- MeSH
- adaptorové proteiny signální transdukční chemie metabolismus MeSH
- aktivace lymfocytů MeSH
- antigen prezentující buňky imunologie MeSH
- B-lymfocyty imunologie metabolismus MeSH
- fosfoproteiny metabolismus MeSH
- HEK293 buňky MeSH
- imunologické synapse chemie MeSH
- lidé MeSH
- malá interferující RNA MeSH
- membránové mikrodomény chemie metabolismus MeSH
- membránové proteiny chemie genetika imunologie metabolismus MeSH
- MHC antigeny II. třídy imunologie metabolismus MeSH
- mitogenem aktivované proteinkinasy metabolismus MeSH
- molekulární sekvence - údaje MeSH
- prezentace antigenu MeSH
- RNA interference MeSH
- sekvence aminokyselin MeSH
- signální transdukce MeSH
- skupina kinas odvozených od src-genu metabolismus MeSH
- src homologní domény MeSH
- T-lymfocyty imunologie MeSH
- tyrosinkinasy chemie metabolismus MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
