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Dental pulp stem cells (DPSCs) are important in tooth physiology, contributing to development, repair, regeneration, and immunomodulatory processes. However, their role in inflammatory mechanisms underlying pulpitis is not well understood. We evaluated the influence of DPSCs stimulated with calcitonin gene-related peptide (CGRP), a proinflammatory neuropeptide, on the expression of mediators released from DPSCs and the effect of these mediators on sensory neuron activity. Human DPSCs were treated with either control media or media containing CGRP (10−8 M) for 7 d, and the conditioned media (CM) containing DPSC-released mediators was collected. The expression of cytokines and chemokines from DPSCs was evaluated by reverse transcription quantitative polymerase chain reaction. The effects of the CM from CGRP-primed DPSCs (primed DPSC-CM) were evaluated on sensory afferents by using primary cultures of mouse trigeminal neurons and an organotypic model of cultured human pulp slices. Mouse trigeminal neurons and human pulp explants were pretreated for 24 h with control or primed DPSC-CM and then stimulated with capsaicin. Afferent activity was measured by quantifying the response to capsaicin via live cell calcium imaging in mouse neurons and CGRP released from pulp explants. Gene expression analysis showed that primed DPSCs overexpressed some proinflammatory cytokines and chemokines, including chemokines CXCL1 and CXCL8, which are both agonists of the receptor CXCR2 expressed in sensory neurons. Primed DPSC-CM increased human pulp sensory afferent activity as compared with control DPSC-CM. Similarly, primed DPSC-CM increased the intensity of calcium responses in cultured mouse trigeminal neurons. Furthermore, the CXCR2 antagonist SB225002 prevented trigeminal neuron sensitization to capsaicin induced by primed DPSC-CM. In conclusion, mediators released by DPSCs, primed with the proinflammatory mediator CGRP, induce neuronal sensitization through CXCR2 receptor. These data suggest that DPSCs might contribute to pain symptoms that develop in pulpitis. [ABSTRACT FROM AUTHOR]

Diabetic foot ulcer (DFU) is an invariably common complication of diabetes, characterized by delayed wound healing process and increased inflammation. Evidence has indicated that paeoniflorin exerts an anti‐inflammatory effect in diabetic retinopathy. The current work was aimed to investigate the effect of paeoniflorin on inflammation and wound healing in DFU. DFU rat models by streptozotocin and skin biopsy punch, as well as high glucose‐treated human immortalized keratinocytes (HaCaT) were established. Levels of blood glucose, wound contraction and proinflammatory cytokine were detected after paeoniflorin administration. Several essential targets associated with the NF‐κB and Nod‐like receptor protein‐3 (NLRP3) signaling pathways were examined. Results showed markedly down‐regulation of interleukin (IL)‐1β, IL‐18 and tumor necrosis factor‐alpha in paeoniflorin‐treated DFU rats. Paeoniflorin decreased the expression levels of chemokine receptor CXCR2, nuclear NF‐κB and p‐IκB (Ser36), as well as increased IκB level. Histological analysis and immunostaining showed lower inflammatory cells with decreased NLRP3 and cleaved caspase‐1 levels following paeoniflorin treatment. Further in vitro evidence confirmed that paeoniflorin efficiently inhibited NLRP3 and NF‐κB‐mediated inflammation in DFU by inhibiting CXCR2. These findings are suggestive of greatly attenuated wound inflammation and better wound healing in paeoniflorin‐treated DFU rats. Our study demonstrates that paeoniflorin is a potential therapeutic agent for DFU. [ABSTRACT FROM AUTHOR]

BackgroundThe functional role of ELR-positive CXC chemokines during viral – induced demyelination was assessed. Inoculation of the neuroattenuated JHM strain of mouse hepatitis virus (JHMV) into the CNS of susceptible mice results in an acute encephalomyelitis that evolves into a chronic demyelinating disease, modeling white matter pathology observed in the human demyelinating disease Multiple Sclerosis.Methodology/Principal FindingsJHMV infection induced the rapid and sustained expression of transcripts specific for the ELR (+) chemokine ligands CXCL1 and CXCL2, as well as their binding receptor CXCR2, which was enriched within the spinal cord during chronic infection. Inhibiting CXCR2 signaling with neutralizing antiserum significantly (p

Aims Atherosclerosis manifests itself as arterial plaques, which lead to heart attacks or stroke. Treatments supporting plaque regression are therefore aggressively pursued. Studies conducted in models in which hypercholesterolaemia is reversible, such as the Reversa mouse model we have employed in the current studies, will be instrumental for the development of such interventions. Using this model,we haveshownthat advanced atherosclerosis regression occurswhenlipid lowering is used in combination with bone-marrowendothelial progenitor cell (EPC) treatment.However, it remains unclear how EPCs home to regressing plaques and how they augment atherosclerosis reversal. Here we identify molecules that support functional responses of EPCs during plaque resolution. Methods and results ChemokinesCXCL1andCX3CL1were detected in the vascularwall of atheroregressingReversa mice, and their cognate receptors CXCR2 and CX3CR1 were observed on adoptively transferred EPCs in circulation. We tested whether CXCL1-CXCR2 and CX3CL1-CX3CR1 axes regulate functional responses of EPCs during plaque reversal. We show that pharmacological inhibition of CXCR2 or CX3CR1, or genetic inactivation of these two chemokine receptors interfered with EPC-mediated advanced atherosclerosis regression.We also demonstrate that CXCR2 directs EPCs to regressing plaques while CX3CR1 controls a paracrine function(s) of these cells. Conclusion CXCR2 and CX3CR1 differentially regulate EPC functional responses during atheroregression. Our study improves understanding of how chemokines and chemokine receptors regulate plaque resolution, which could determine the effectiveness of interventions reducing complications of atherosclerosis. [ABSTRACT FROM AUTHOR]

Thrombin at low doses is an endogenous mediator of protection in ischaemic and haemorrhagic models of stroke. However, the mechanism of thrombin-induced protection remains unclear. Recently accumulating evidence has shown that astrocytes play an important role in the brain after injury. We report that thrombin and thrombin receptor agonist peptide (TRag) up-regulated secretion of the chemokine growth-regulated oncogene/cytokine-induced neutrophil chemoattractant-1 (GRO/CINC-1) in primary rat astrocytes in a concentration-dependent manner. However, we found no increase of interleukin (IL)-6, IL-1β and tumour necrosis factor-α secretion. Protease-activated receptor 1 (PAR-1)-induced GRO/CINC-1 release was mainly mediated by c-Jun N-terminal kinase (JNK) activation. Extracellular signal-regulated kinase 1/2 might be partially involved, but not p38 mitogen-activated protein kinase. Further studies demonstrated that PAR-1 activation, as well as application of recombinant GRO/CINC-1, protected astrocytes from C2-ceramide-induced cell death. Protection occurred with suppression of cytochrome c release from mitochondria. The inhibition of cytochrome c release was largely reduced by the antagonist of chemokine receptor CXCR2, SB-332235. Importantly, a specific JNK inhibitor significantly abolished the protective action of PAR-1. These results demonstrate for the first time that PAR-1 plays an important role in anti-apoptosis in the brain by regulating the release of chemokine GRO/CINC-1, which gives a feedback through its receptor CXCR2 to preserve astrocytes from toxic insults. [ABSTRACT FROM AUTHOR]

System hypertension is a major risk factor for cardiac hypertrophy and heart failure. Our recent findings reveal that the ablation or inhibition of C-X-C chemokine receptor (CXCR) 2 blocks this process in mice; however, it is not clear whether the pharmacological inhibition of CXCR2 attenuates hypertension and subsequent cardiac remodeling in spontaneously hypertensive rats (SHRs). In the present study, we showed that chemokines (CXCL1 and CXCL2) and CXCR2 were significantly upregulated in SHR hearts compared with Wistar–Kyoto rat (WKY) hearts. Moreover, the administration of CXCR2-specific inhibitor N -(2-hydroxy-4-nitrophenyl)- N′ -(2-bromophenyl)-urea (SB225002) in SHRs (at 2 months of age) for an additional 4 months significantly suppressed the elevation of blood pressure, cardiac myocyte hypertrophy, fibrosis, inflammation, and superoxide production and improved heart dysfunction in SHRs compared with vehicle-treated SHRs. SB225002 treatment also reduced established hypertension, cardiac remodeling and contractile dysfunction. Moreover, CXCR2-mediated increases in the recruitment of Mac-2-positive macrophages, proinflammatory cytokines, vascular permeability and ROS production in SHR hearts were markedly attenuated by SB225002. Accordingly, the inhibition of CXCR2 by SB225002 deactivates multiple signaling pathways (AKT/mTOR, ERK1/2, STAT3, calcineurin A, TGF-β/Smad2/3, NF-κB-p65, and NOX). Our results provide new evidence that the chronic blocking of CXCR2 activation attenuates progression of cardiac hypertrophic remodeling and dysfunction in SHRs. These findings may be of value in understanding the benefits of CXCR2 inhibition for hypertensive cardiac hypertrophy and provide further support for the clinical application of CXCR2 inhibitors for the prevention and treatment of heart failure. • Blocking of CXCR2 activation attenuates hypertension and cardiac remodeling in spontaneously hypertensive rats. • Administration of a CXCR2 inhibitor SB225002 significantly inhibits inflammation and oxidative stress. • Inhibition of CXCR2 reduces activation of AKT/mTOR, TGF-β/Smad2/3, and NF-kB signaling pathways. [ABSTRACT FROM AUTHOR]