scholarly journals Hemokinin-1 as a Mediator of Arthritis-Related Pain via Direct Activation of Primary Sensory Neurons

2021 ◽  
Vol 11 ◽  
Author(s):  
Éva Borbély ◽  
Ágnes Hunyady ◽  
Krisztina Pohóczky ◽  
Maja Payrits ◽  
Bálint Botz ◽  
...  
Keyword(s):  
Sensory Neurons ◽  
Immune Cell ◽  
Active Immunization ◽  
Fluorescent Imaging ◽  
Laser Speckle ◽  
Myeloperoxidase Activity ◽  
Primary Sensory Neurons ◽  
Protein Extravasation ◽  
Deficient Mice

The tachykinin hemokinin-1 (HK-1) is involved in immune cell development and inflammation, but little is known about its function in pain. It acts through the NK1 tachykinin receptor, but several effects are mediated by a yet unidentified target. Therefore, we investigated the role and mechanism of action of HK-1 in arthritis models of distinct mechanisms with special emphasis on pain. Arthritis was induced by i.p. K/BxN serum (passive transfer of inflammatory cytokines, autoantibodies), intra-articular mast cell tryptase or Complete Freund’s Adjuvant (CFA, active immunization) in wild type, HK-1- and NK1-deficient mice. Mechanical- and heat hyperalgesia determined by dynamic plantar esthesiometry and increasing temperature hot plate, respectively, swelling measured by plethysmometry or micrometry were significantly reduced in HK-1-deleted, but not NK1-deficient mice in all models. K/BxN serum-induced histopathological changes (day 14) were also decreased, but early myeloperoxidase activity detected by luminescent in vivo imaging increased in HK-1-deleted mice similarly to the CFA model. However, vasodilation and plasma protein extravasation determined by laser Speckle and fluorescent imaging, respectively, were not altered by HK-1 deficiency in any models. HK-1 induced Ca2+-influx in primary sensory neurons, which was also seen in NK1-deficient cells and after pertussis toxin-pretreatment, but not in extracellular Ca2+-free medium. These are the first results showing that HK-1 mediates arthritic pain and cellular, but not vascular inflammatory mechanisms, independently of NK1 activation. HK-1 activates primary sensory neurons presumably via Ca2+ channel-linked receptor. Identifying its target opens new directions to understand joint pain leading to novel therapeutic opportunities.

scholarly journals Upregulation of class I major histocompatibility complex gene expression in primary sensory neurons, satellite cells, and Schwann cells of mice in response to acute but not latent herpes simplex virus infection in vivo.

1994 ◽  
Vol 180 (3) ◽  
pp. 841-850 ◽  
Author(s):  
R A Pereira ◽  
D C Tscharke ◽  
A Simmons
Keyword(s):  
Gene Expression ◽  
Major Histocompatibility Complex ◽  
Schwann Cells ◽  
Sensory Neurons ◽  
Neural Tissue ◽  
Class I ◽  
Primary Sensory Neurons ◽  
Histocompatibility Complex ◽  
Simplex Virus

Major histocompatibility complex (MHC) deficiency is typical of almost all resident cells in normal neural tissue. However, CD8+ T cells, which recognize antigenic peptides in the context of class I MHC molecules, are known to mediate clearance of herpes simplex virus (HSV) from spinal ganglia of experimentally infected mice, leading to the hypothesis that class I expression in the peripheral nervous system must be upregulated in response to HSV infection. In addressing this hypothesis it is shown, in BALB/c (H-2d) mice, that normally deficient class I transcripts transiently accumulate in peripheral nerve Schwann cells, ganglionic satellite cells, and primary sensory neurons, indicating that in each of these cell types class I expression is regulated at the transcriptional level in vivo. Furthermore, for 3-4 wk after infection, H-2Kd/Dd antigens are expressed by satellite and Schwann cells but not neurons, suggesting additional posttranscriptional regulation of class I synthesis in neurons. Alternatively, the class I RNAs induced in neurons may not be derived from classical class I genes. Factors regulating H-2 class I expression emanate from within infected ganglia, probably from infected neurons themselves. However, induction of class I molecules was not maintained during latency, when viral gene expression in neurons is restricted to a single region within the virus repeats. These data have implications for the long-term survival of cells in HSV-infected neural tissue.

scholarly journals Cell Surface Expression of H2 Antigens on Primary Sensory Neurons in Response to Acute but Not Latent Herpes Simplex Virus Infection In Vivo

1999 ◽  
Vol 73 (8) ◽  
pp. 6484-6489 ◽  
Author(s):  
Rosemarie A. Pereira ◽  
Anthony Simmons
Keyword(s):  
Herpes Simplex Virus ◽  
Herpes Simplex ◽  
Cell Surface ◽  
Sensory Neurons ◽  
Cell Surface Expression ◽  
Immunogold Electron Microscopy ◽  
Primary Sensory Neurons ◽  
Mhc I ◽  
Simplex Virus

ABSTRACT CD8+ T lymphocytes and class I major histocompatibility complex (MHC-I) molecules profoundly influence the severity of neuronal herpes simplex virus (HSV) infection in experimentally infected mice. Paradoxically, neurons are classically regarded as MHC-I deficient. However, it is shown here that H2-encoded heavy chains (αCs) and their associated light chain, β2 microglobulin, are present on the surfaces of primary sensory neurons recovered from sensory ganglia within 1 to 2 weeks of HSV infection. During this time, some neurons are found to be tightly associated with T cells in vivo. Prior data showed that termination of productive HSV infection in the peripheral nervous system is not dependent on cell-mediated lysis of infected neurons. Consistent with these data, immunogold electron microscopy showed that the density of cell surface H2 on neurons is an order of magnitude lower than on satellite glia, which is predicted to favor a noncytolytic CD8 cell response.

scholarly journals Immunodetection of prostaglandin D synthase: conditions of localization in a defined subclass of primary sensory neurons.

1995 ◽  
Vol 43 (7) ◽  
pp. 681-687 ◽  
Author(s):  
M F Vesin ◽  
B Droz
Keyword(s):  
Sensory Neurons ◽  
Ganglion Cells ◽  
Ultrastructural Level ◽  
Primary Sensory Neurons ◽  
Small Class ◽  
Thin Sections ◽  
Class B ◽  
Triton X

Prostaglandin (PG) D2 is synthesized by primary sensory neurons grown in vitro. The question can be raised of whether the entire population or only a particular subpopulation of primary sensory neurons synthesizes PGD2 in vivo. To clarify this issue it was necessary to demonstrate that PGD synthase activity persists in fresh dorsal root ganglion (DRG) cryostat slices by characterizing newly formed PGD2 from [14C]-arachidonic acid, and to determine by immunocytochemistry and to identify at the ultrastructural level the neuron subpopulation expressing glutathione (GSH)-independent PGD synthase. Among the various procedures tested, the most intense, selective, and reproducible immunostaining pattern was obtained after periodate-lysine-formaldehyde fixation in phosphate buffer, permeabilization with 0.25% Triton X-100, and incubation with 10 micrograms/ml purified antibodies. Under these conditions, a subpopulation of small Class B ganglion cells was strongly immunoreactive, whereas adjacent control sections treated with absorbed antibodies or with non-immune rabbit or goat serum were unreactive. To identify the subclass of the immunoreactive small Class B neurons, immunostained vibratome slices of DRG were embedded in Epon. Ganglion cell bodies loaded with immunoprecipitates in superficially cut sections were first identified and then ultrastructurally analyzed in thin sections taken from a deeper level to obtain improved preservation of the cell architecture. This procedure enabled us to demonstrate that GSH-independent PGD synthase is accumulated in Subclass B1 primary sensory neurons.

scholarly journals Infection with an H2 recombinant herpes simplex virus vector results in expression of MHC class I antigens on the surfaces of human neuroblastoma cells in vitro and mouse sensory neurons in vivo

2000 ◽  
Vol 81 (10) ◽  
pp. 2375-2383 ◽  
Author(s):  
Allison Abendroth ◽  
Anthony Simmons ◽  
Stacey Efstathiou ◽  
Rosemarie A. Pereira
Keyword(s):  
Cell Surface ◽  
Sensory Neurons ◽  
Neuroblastoma Cells ◽  
Primary Sensory Neurons ◽  
Human Neuroblastoma Cells ◽  
Human Neuroblastoma ◽  
Mhc I ◽  
Simplex Virus

The majority of neurons in herpes simplex virus (HSV)-infected murine sensory ganglia are transiently induced to express MHC-I antigens at the cell surface, whereas only a minority are themselves productively infected. The aim of the current work was to determine whether MHC-I antigens can be expressed on the surfaces of infected neurons in addition to their uninfected neighbours. To address this aim a recombinant HSV type 1 strain, S-130, was used to deliver a mouse H2Kd gene, under control of the HCMV IE-1 promoter/enhancer, into human neuroblastoma cells in vitro and mouse primary sensory neurons in vivo. S-130 expressed H2Kd antigens on the surfaces of IMR-32 cells, a human neuroblastoma cell line that expresses very low levels of MHC-I constitutively. In K562 cells, which do not express MHC-I constitutively, H2Kd and β2-microglobulin (β2m) were shown to be co-expressed at the cell surface following S-130 infection. This observation was taken as evidence that class I heavy chain (αC) molecules encoded by the expression cassette in the HSV genome were transported to the cell surface as stable complexes with β2m. Significantly, after introduction of S-130 into flank skin, H2Kd antigens were detected on the surfaces of primary sensory neurons in ganglia innervating the inoculation site. Our data show that HSV-infected murine primary sensory neurons and human neuroblastoma cells are capable of expressing cell-surface MHC-I molecules encoded by a transgene. From this, we infer that up-regulation of αC expression is, in principle, sufficient to overcome potential impediments to neuronal cell surface expression of MHC-I complexes.

scholarly journals IL-15Rα-Independent IL-15 Signaling in Non-NK Cell-Derived IFNγ Driven Control of Listeria monocytogenes

2021 ◽  
Vol 12 ◽  
Author(s):  
Madhuparna Nandi ◽  
Mitterrand Muamba Moyo ◽  
Sakina Orkhis ◽  
Jeanne Masunga Faida Mobulakani ◽  
Marc-André Limoges ◽  
...  
Keyword(s):  
Listeria Monocytogenes ◽  
Immune Cell ◽  
Nk Cell ◽  
Myeloid Cell ◽  
Inflammatory Monocytes ◽  
Receptor Chain ◽  
Bacterial Uptake ◽  
Deficient Mice

Interleukin-15, produced by hematopoietic and parenchymal cells, maintains immune cell homeostasis and facilitates activation of lymphoid and myeloid cell subsets. IL-15 interacts with the ligand-binding receptor chain IL-15Rα during biosynthesis, and the IL-15:IL-15Rα complex is trans-presented to responder cells that express the IL-2/15Rβγc complex to initiate signaling. IL-15-deficient and IL-15Rα-deficient mice display similar alterations in immune cell subsets. Thus, the trimeric IL-15Rαβγc complex is considered the functional IL-15 receptor. However, studies on the pathogenic role of IL-15 in inflammatory and autoimmune diseases indicate that IL-15 can signal independently of IL-15Rα via the IL-15Rβγc dimer. Here, we compared the ability of mice lacking IL-15 (no signaling) or IL-15Rα (partial/distinct signaling) to control Listeria monocytogenes infection. We show that IL-15-deficient mice succumb to infection whereas IL-15Rα-deficient mice clear the pathogen as efficiently as wildtype mice. IL-15-deficient macrophages did not show any defect in bacterial uptake or iNOS expression in vitro. In vivo, IL-15 deficiency impaired the accumulation of inflammatory monocytes in infected spleens without affecting chemokine and pro-inflammatory cytokine production. The inability of IL-15-deficient mice to clear L. monocytogenes results from impaired early IFNγ production, which was not affected in IL-15Rα-deficient mice. Administration of IFNγ partially enabled IL-15-deficient mice to control the infection. Bone marrow chimeras revealed that IL-15 needed for early bacterial control can originate from both hematopoietic and non-hematopoietic cells. Overall, our findings indicate that IL-15-dependent IL-15Rα-independent signaling via the IL-15Rβγc dimeric complex is necessary and sufficient for the induction of IFNγ from sources other than NK/NKT cells to control bacterial pathogens.

scholarly journals Activation of NLRP3 Inflammasome Complexes by Beta-Tricalcium Phosphate Particles and Stimulation of Immune Cell Migration in vivo

2021 ◽  
pp. 1-11
Author(s):  
Kouji Maruyama ◽  
Jin-Yan Cheng ◽  
Hidee Ishii ◽  
Yu Takahashi ◽  
Vincent Zangiacomi ◽  
...  
Keyword(s):  
Cell Migration ◽  
Tricalcium Phosphate ◽  
Nlrp3 Inflammasome ◽  
Immune Cell ◽  
Dependent Manner ◽  
Potassium Efflux ◽  
Beta Tricalcium Phosphate ◽  
Immune Cell Migration ◽  
Deficient Mice

Beta-tricalcium phosphate (β-TCP) serves as a bone substitute in clinical practice because it is resorbable, biocompatible, osteointegrative, and osteoconductive. Particles of β-TCP are also inflammatory mediators although the mechanism of this function has not been fully elucidated. Regardless, the ability of β-TCP to stimulate the immune system might be useful for immunomodulation. The present study aimed to determine the effects of β-TCP particles on NLR family pyrin domain containing 3 (NLRP3) inflammasome complexes. We found that β-TCP activates NLRP3 inflammasomes, and increases interleukin (IL)-1β production in primary cultured mouse dendritic cells (DCs) and macrophages, and human THP-1 cells in caspase-1 dependent manner. In THP-1 cells, β-TCP increased also IL-18 production, and NLRP3 inflammasome activation by β-TCP depended on phagocytosis, potassium efflux, and reactive oxygen species (ROS) generation. We also investigated the effects of β-TCP in wild-type and NLRP3-deficient mice in vivo. Immune cell migration around subcutaneously injected β-TCP particles was reduced in NLRP3-deficient mice. These findings suggest that the effects of β-TCP particles in vivo are at least partly mediated by NLRP3 inflammasome complexes.

scholarly journals Identification of the nonreceptor tyrosine kinase MATK/CHK as an essential regulator of immune cells using Matk/CHK-deficient mice

Blood ◽  
2006 ◽  
Vol 108 (3) ◽  
pp. 904-907 ◽  
Author(s):  
Byeong-Chel Lee ◽  
Shalom Avraham ◽  
Akira Imamoto ◽  
Hava Karsenty Avraham
Keyword(s):  
Tyrosine Kinase ◽  
Immune Cell ◽  
Side Population ◽  
Wild Type ◽  
Spleen Cells ◽  
Nonreceptor Tyrosine Kinase ◽  
Ifn Γ ◽  
Deficient Mice ◽  
Cell Colony

Abstract Matk/CHK knockout mice were reported to show no apparent phenotypic abnormalities. This was thought to be due to the homologous kinase Csk that compensates for Matk/CHK. Here, we present the first evidence that the nonreceptor tyrosine kinase, Matk/CHK, is an important modulator of immune cell signaling. We found that the frequency of primitive hematopoietic cells, the side population c-kit+ Lin– Sca-1+ (SPKLS) cells, in Matk/CHK–/– mice was increased 2.2-fold compared with the control mice. Moreover, Matk/CHK deficiency led to significantly higher pre–B cell colony formation following IL-7 stimulation. Interestingly, when mice received the in vivo antigen challenge of TNP-ovalbumin followed by restimulation, the Matk/CHK–/– lymph node and spleen cells produced significantly lower IFN-γ levels compared with the respective wild-type cells. Our study indicates that Matk/CHK is not functionally redundant with Csk, and that this tyrosine kinase plays an important role as a regulator of immunologic responses.

scholarly journals Deoxyribonuclease 1-Mediated Clearance of Circulating Chromatin Prevents From Immune Cell Activation and Pro-inflammatory Cytokine Production, a Phenomenon Amplified by Low Trap1 Activity: Consequences for Systemic Lupus Erythematosus

2021 ◽  
Vol 12 ◽  
Author(s):  
Jasmin Felux ◽  
Annika Erbacher ◽  
Magali Breckler ◽  
Roxane Hervé ◽  
Delphine Lemeiter ◽  
...  
Keyword(s):  
Immune Cells ◽  
Lupus Erythematosus ◽  
Cell Activation ◽  
Immune Cell ◽  
Wild Type ◽  
Systemic Lupus ◽  
Immune Cell Activation ◽  
Deficient Mice

Increased concentrations of circulating chromatin, especially oligo-nucleosomes, are observed in sepsis, cancer and some inflammatory autoimmune diseases like systemic lupus erythematosus (SLE). In SLE, circulating nucleosomes mainly result from increased apoptosis and decreased clearance of apoptotic cells. Once released, nucleosomes behave both as an autoantigen and as a damage-associated molecular pattern (DAMP) by activating several immune cells, especially pro-inflammatory cells. Deoxyribonuclease 1 (DNase1) is a major serum nuclease whose activity is decreased in mouse and human lupus. Likewise, the mitochondrial chaperone tumor necrosis factor (TNF) receptor-associated protein-1 (Trap1) protects against oxidative stress, which is increased in SLE. Here, using wild type, DNase1-deficient and DNase1/Trap1-deficient mice, we demonstrate that DNase1 is a major serum nuclease involved in chromatin degradation, especially when the plasminogen system is activated. In vitro degradation assays show that chromatin digestion is strongly impaired in serum from DNase1/Trap1-deficient mice as compared to wild type mice. In vivo, after injection of purified chromatin, clearance of circulating chromatin is delayed in DNase1/Trap1-deficient mice in comparison to wild type mice. Since defective chromatin clearance may lead to chromatin deposition in tissues and subsequent immune cell activation, spleen cells were stimulated in vitro with chromatin. Splenocytes were activated by chromatin, as shown by interleukin (IL)-12 secretion and CD69 up-regulation. Moreover, cell activation was exacerbated when Trap1 is deficient. Importantly, we also show that cytokines involved in lupus pathogenesis down-regulate Trap1 expression in splenocytes. Therefore, combined low activities of both DNase1 and Trap1 lead to an impaired degradation of chromatin in vitro, delayed chromatin clearance in vivo and enhanced activation of immune cells. This situation may be encountered especially, but not exclusively, in SLE by the negative action of cytokines on Trap1 expression.

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