Mast cells can be found in close proximity to peripheral nerve endings where, upon activation, they release a broad range of pro-inflammatory cytokines and chemokines. However, the precise mechanism ...underlying this so-called neurogenic inflammation and associated pain has remained elusive. Here we report that the mast-cell-specific receptor Mrgprb2 mediates inflammatory mechanical and thermal hyperalgesia and is required for recruitment of innate immune cells at the injury site. We also found that the neuropeptide substance P (SP), an endogenous agonist of Mrgprb2, facilitates immune cells’ migration via Mrgprb2. Furthermore, SP activation of the human mast cell led to the release of multiple pro-inflammatory cytokines and chemokines via the human homolog MRGPRX2. Surprisingly, the SP-mediated inflammatory responses were independent of its canonical receptor, neurokinin-1 receptor (NK-1R). These results identify Mrgprb2/X2 as an important neuroimmune modulator and a potential target for treating inflammatory pain.
•The mast cell receptor Mrgprb2 is required for neurogenic inflammatory pain•Substance P (SP) recruits immune cells via Mrgprb2 independent of the NK-1 receptor•SP activation of Mrgprb2 and its human ortholog MRGPRX2 releases cytokines•Mrgprb2/X2 is a target for treating pain
Green et al. show that activation of the mast cell receptor Mrgprb2/X2 by the neuropeptide substance P leads to cytokine release and recruitment of immune cells contributing to inflammatory pain.
Classical itch studies have focused on immunoglobulin E (IgE)-mediated mast cell activation and histamine release. Recently, members of the Mas-related G-protein-coupled receptor (Mrgpr) family have ...been identified as mast cell receptors, but their role in itch is unclear. Here, we report that mast cell activation via Mrgprb2 evoked non-histaminergic itch in mice independently of the IgE-Fc epsilon RI (FcεRI)-histamine axis. Compared with IgE-FcεRI stimulation, Mrgprb2 activation of mast cells was distinct in both released substances (histamine, serotonin, and tryptase) and the pattern of activated itch-sensory neurons. Mrgprb2 deficiency decreased itch in multiple preclinical models of allergic contact dermatitis (ACD), a pruritic inflammatory skin disorder, and both mast cell number and PAMP1-20 concentrations (agonist of the human Mrgprb2 homolog, MRGPRX2) were increased in human ACD skin. These findings suggest that this pathway may represent a therapeutic target for treating ACD and mast-cell-associated itch disorders in which antihistamines are ineffective.
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•Mrgprb2 is a mast cell (MC)-specific receptor that mediates non-histaminergic itch•Compared to FcεRI, Mrgprb2 activation releases more tryptase and less monoamines•Mrgprb2 activation of MCs excites non-histaminergic itch-sensory neurons•MRGPRX2 may be a target for allergic contact dermatitis-associated itch in humans
Classical itch studies have focused on IgE-mediated mast cell activation and histamine release. Meixiong et al. demonstrate that mast cell activation through the receptor Mrgprb2 contributes to non-histaminergic pruritus. Compared with IgE-FcεRI signaling, Mrgprb2-activated mast cells released more tryptase and excited a distinct itch-sensory neuron population. Mast-cell-associated Mrgprs may be therapeutic targets for itch associated with allergic contact dermatitis.
Telomere dysfunction causes alveolar stem cell failure Alder, Jonathan K.; Barkauskas, Christina E.; Limjunyawong, Nathachit ...
Proceedings of the National Academy of Sciences - PNAS,
04/2015, Letnik:
112, Številka:
16
Journal Article
Recenzirano
Odprti dostop
Significance Idiopathic pulmonary fibrosis and emphysema are leading causes of mortality, but there are no effective therapies. Mutations in telomerase are the most common identifiable risk factor ...for idiopathic pulmonary fibrosis. They also predispose to severe emphysema in smokers, occurring at a frequency similar to α-1 antitrypsin deficiency. The work shown here points to alveolar stem cell senescence as a driver of these pathologies. Epithelial stem cell failure was associated with secondary inflammatory recruitment and exquisite susceptibility to injury from “second hits.” The findings suggest that efforts to reverse the stem cell failure state directly, rather than its secondary consequences, may be an effective therapy approach in telomere-mediated lung disease.
Telomere syndromes have their most common manifestation in lung disease that is recognized as idiopathic pulmonary fibrosis and emphysema. In both conditions, there is loss of alveolar integrity, but the underlying mechanisms are not known. We tested the capacity of alveolar epithelial and stromal cells from mice with short telomeres to support alveolar organoid colony formation and found that type 2 alveolar epithelial cells (AEC2s), the stem cell-containing population, were limiting. When telomere dysfunction was induced in adult AEC2s by conditional deletion of the shelterin component telomeric repeat-binding factor 2, cells survived but remained dormant and showed all the hallmarks of cellular senescence. Telomere dysfunction in AEC2s triggered an immune response, and this was associated with AEC2-derived up-regulation of cytokine signaling pathways that are known to provoke inflammation in the lung. Mice uniformly died after challenge with bleomycin, underscoring an essential role for telomere function in AEC2s for alveolar repair. Our data show that alveoloar progenitor senescence is sufficient to recapitulate the regenerative defects, inflammatory responses, and susceptibility to injury that are characteristic of telomere-mediated lung disease. They suggest alveolar stem cell failure is a driver of telomere-mediated lung disease and that efforts to reverse it may be clinically beneficial.
Migraine ranks among the most prevalent disorders worldwide, leading to disability and decreased quality of life in patients. Recently, neurogenic inflammation has been recognized as a potential ...underlying pathology contributing to the migraine pain pathway. Mast cells reside in the meninges and have been implicated in contributing to the pathophysiology of migraine. Here we report for the first time that the mouse Mas-Related G-protein-coupled Receptor B2 (MrgprB2), is expressed on meningeal connective tissue mast cells and contributes to Pituitary Adenylate Cyclase Activating Peptide (PACAP)-induced migraine-like pain behavior. We also found that PACAP was able to dose-dependently lead to enzyme release from human mast cells via activation of MRGPRX2; the human homolog of MrgprB2. Using a transgenic MRGPRX2 mouse, we observed significant increases in PACAP-induced migraine-like pain behavior in MRGPRX2
mice vs mice lacking the receptor. These results reveal both MrgprB2 and MRGPRX2 as important contributors to neuropeptide-induced migraine pain.
Quorum-sensing molecules (QSMs) are secreted by bacteria to signal population density. Upon reaching a critical concentration, QSMs induce transcriptional alterations in bacteria, which enable ...virulence factor expression and biofilm formation. It is unclear whether mammalian hosts can recognize QSMs to trigger responsive antibacterial immunity. We report that mouse mast-cell-specific G-protein-coupled receptor Mrgprb2 and its human homolog MRGPRX2 are receptors for Gram-positive QSMs, including competence-stimulating peptide (CSP)-1. CSP-1 activates Mrgprb2 and MRGPRX2, triggering mast cell degranulation, which inhibits bacterial growth and prevents biofilm formation. Such antibacterial functions are reduced in Mrgprb2-deficient mast cells, while wild-type mast cells fail to inhibit the growth of bacterial strains lacking CSP-1. Mrgprb2-knockout mice exhibit reduced bacterial clearance, while pharmacologically activating Mrgprb2 in vivo eliminates bacteria and improves disease score. These findings identify a host defense mechanism that uses QSMs as an “Achilles heel” and suggest MRGPRX2 as a potential therapeutic target for controlling bacterial infections.
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•The mammalian receptor Mrgprb2 and MRGPRX2 can detect bacterial QSMs•QSM detection by Mrgprb2 and MRGPRX2 in mast cells elicits antibacterial mediator release•Mrgprb2 recognition of QSMs is critical for an effective immune response to bacteria•Pharmacologic activation of Mrgprb2 and MRGPRX2 enhances bacterial clearance
Bacteria use quorum-sensing signaling for cross-species communication. Pundir et al. report that host mast cells detect Gram-positive-bacteria-derived quorum-sensing molecules via the Mrgpr receptors. Mrgpr activation triggers antibacterial activity and immune cell recruitment to efficiently clear bacteria, while animals deficient in Mrgpr are hypersusceptible to bacterial infection.
Over 100 million women use progesterone therapies worldwide. Despite having immunomodulatory and repair properties, their effects on the outcome of viral diseases outside of the reproductive tract ...have not been evaluated. Administration of exogenous progesterone (at concentrations that mimic the luteal phase) to progesterone-depleted adult female mice conferred protection from both lethal and sublethal influenza A virus (IAV) infection. Progesterone treatment altered the inflammatory environment of the lungs, but had no effects on viral load. Progesterone treatment promoted faster recovery by increasing TGF-β, IL-6, IL-22, numbers of regulatory Th17 cells expressing CD39, and cellular proliferation, reducing protein leakage into the airway, improving pulmonary function, and upregulating the epidermal growth factor amphiregulin (AREG) in the lungs. Administration of rAREG to progesterone-depleted females promoted pulmonary repair and improved the outcome of IAV infection. Progesterone-treatment of AREG-deficient females could not restore protection, indicating that progesterone-mediated induction of AREG caused repair in the lungs and accelerated recovery from IAV infection. Repair and production of AREG by damaged respiratory epithelial cell cultures in vitro was increased by progesterone. Our results illustrate that progesterone is a critical host factor mediating production of AREG by epithelial cells and pulmonary tissue repair following infection, which has important implications for women's health.
Chronic pruritus is a prominent symptom of allergic contact dermatitis (ACD) and represents a huge unmet health problem. However, its underlying cellular and molecular mechanisms remain largely ...unexplored. TRPC3 is highly expressed in primary sensory neurons and has been implicated in peripheral sensitization induced by proinflammatory mediators. Yet, the role of TRPC3 in acute and chronic itch is still not well defined. Here, we show that, among mouse trigeminal ganglion (TG) neurons, Trpc3 mRNA is predominantly expressed in nonpeptidergic small diameter TG neurons of mice. Moreover, Trpc3 mRNA signal was present in most presumptively itch sensing neurons. TRPC3 agonism induced TG neuronal activation and acute nonhistaminergic itch-like and pain-like behaviors in naive mice. In addition, genetic deletion of Trpc3 attenuated acute itch evoked by certain common nonhistaminergic pruritogens, including endothelin-1 and SLIGRL-NH2. In a murine model of contact hypersensitivity (CHS), the Trpc3 mRNA expression level and function were upregulated in the TG after CHS. Pharmacological inhibition and global knockout of Trpc3 significantly alleviated spontaneous scratching behaviors without affecting concurrent cutaneous inflammation in the CHS model. Furthermore, conditional deletion of Trpc3 in primary sensory neurons but not in keratinocytes produced similar antipruritic effects in this model. These findings suggest that TRPC3 expressed in primary sensory neurons may contribute to acute and chronic itch through a histamine independent mechanism and that targeting neuronal TRPC3 might benefit the treatment of chronic itch associated with ACD and other inflammatory skin disorders.
Pressure-volume (PV) curves constructed over the entire lung volume range can reliably detect functional changes in mouse models of lung diseases. In the present study, we constructed full-range PV ...curves in healthy and elastase-treated mice using either a classic manually operated technique or an automated approach using a computer-controlled piston ventilator flexiVent FX; Scientific Respiratory Equipment (SCIREQ), Montreal, Quebec, Canada. On the day of the experiment, subjects were anesthetized, tracheotomized, and mechanically ventilated. Following an initial respiratory mechanics scan and degassing of the lungs with 100% O
, full-range PV curves were constructed using either the classic or the automated technique. In control mice, superimposable curves were obtained, and statistical equivalence was attained between the two methodologies. In the elastase-treated ones, where significant changes in respiratory mechanics and lung volumes were expected, very small differences were observed between the two techniques, and the criteria for statistical equivalence were met in two out of four parameters assessed. The automated technique was adapted to rats and used to estimate the functional residual capacity (FRC) by volume subtraction. This novel approach generated FRC estimates consistent with the literature, with added accuracy relative to the existing method in diseased subjects. In conclusion, the automated technique generated full-range PV curves that were equivalent or very close to those obtained with the classic method under physiological or severe pathological conditions. The automation facilitated some technical aspects of the procedure, eased its use across species, and helped derive a more accurate estimate of FRC in preclinical models of respiratory disease.
Partial and full-range pressure-volume (PV) curves are frequently used to characterize lung disease models. Whereas automated techniques exist to construct partial PV curves, a manually operated approach is classically employed to build the full-range ones. In this study, the full-range PV curve technique was automated using a computer-controlled piston ventilator. The automation simplified the technique, facilitated its extension to other species, and inspired a novel way of estimating the functional residual capacity in laboratory rodents.
The molecular control of osteoclast formation is still not clearly elucidated. Here, we show that a process of cell recognition mediated by Siglec15-TLR2 binding is indispensable and occurs prior to ...cell fusion in RANKL-mediated osteoclastogenesis. Siglec15 has been shown to regulate osteoclastic bone resorption. However, the receptor for Siglec15 has not been identified, and the signaling mechanism involving Siglec15 in osteoclast function remains unclear. We found that Siglec15 bound sialylated TLR2 as its receptor and that the binding of sialylated TLR2 to Siglec15 in macrophages committed to the osteoclast-lineage initiated cell fusion for osteoclast formation, in which sialic acid was transferred by the sialyltransferase ST3Gal1. Interestingly, the expression of Siglec15 in macrophages was activated by M-CSF, whereas ST3Gal1 expression was induced by RANKL. Both Siglec15-specific deletion in macrophages and intrafemoral injection of sialidase abrogated cell recognition and reduced subsequent cell fusion for the formation of osteoclasts, resulting in increased bone formation in mice. Thus, our results reveal that cell recognition mediated by the binding of sialylated TLR2 to Siglec15 initiates cell fusion for osteoclast formation.
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