Peripheral Inflammatory Cells Research Articles

Engineered Extracellular Vesicle-Based Nanoformulations That Coordinate Neuroinflammation and Immune Homeostasis, Enhancing Parkinson's Disease Therapy.

Although conventional intervention to microglia can mitigate neuroinflammation in the short term, immune disorders by peripheral inflammatory cells can infiltrate continuously, resulting in an overactivated immune microenvironment of Parkinson's disease (PD). Here, we design engineered extracellular vesicle-based nanoformulations (EVNs) to address multiple factors for the management of PD. Specifically, EVN is developed by coating CCR2-enriched mesenchymal stem cell-derived extracellular vesicles (MSCCCR2 EVs) onto a dihydrotanshinone I-loaded nanocarrier (MSeN-DT). The MSCCCR2 EVs (the shell of EVN) can actively show homing to specific chemokines CCL2 in the substantia nigra, which enables them to block the infiltration of peripheral inflammatory cells. Interestingly, MSeN-DT (the core of EVN) can promote the Nrf2-GPX4 pathway for the suppression of the source of inflammation by inhibiting ferroptosis in microglia. In the PD model mice, a satisfactory therapeutic effect is achieved, with inhibition of peripheral inflammatory cell infiltration, precise regulation of inflammatory microglia in the substantia nigra, as well as promotion of behavioral improvement and repairing damaged neurons. In this way, the combinatorial code of alleviation of inflammation and modulation of immune homeostasis can reshape the immune microenvironment in PD, which bridges internal anti-inflammatory and external immunity. This finding reveals a comprehensive therapeutic paradigm for PD that breaks the vicious cycle of immune overactivation.

High peripheral neutrophil and monocyte count distinguishes renal cell carcinoma from renal angiomyolipoma and predicts poor prognosis of renal cell carcinoma

BackgroundThe presence of peripheral inflammatory cells has been linked to the prognosis of cancer. This study aims to investigate the distinct roles of absolute neutrophil count (ANC) and absolute monocyte count (AMC) in differentiating renal cell carcinoma (RCC) from renal angiomyolipoma (RAML), as well as their prognostic significance in RCC. MethodsWe conducted a comprehensive analysis of peripheral immune cell data, clinicopathological data, and tumor characteristics in patients diagnosed with RCC or RAML from January 2015 to December 2021. Receiver operating characteristic (ROC) curves, as well as univariate and multivariate analyses, were employed to assess the diagnostic utility of AMC and ANC in differentiating between RCC and RAML. Kaplan-Meier curve analysis was used to study the survival of RCC patients with different AMC and ANC. The prognostic value of AMC and ANC in RCC was investigated using COX univariate and multivariate analysis. The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases were used for bioinformatic correlation analysis. ResultsA total of 1120 eligible patients were included in the study. The mean preoperative AMC and ANC in patients with RCC were found to be significantly higher compared to those in patients with RAML (P = 0.001 and P < 0.001, respectively). High preoperative AMC and ANC significantly correlated with smoking history, tumor length, gross hematuria, and high T Stage, N stage, and pathological grade. In multivariate analyses, an ANC> 3.205 *10^9/L was identified to be independently associated with the presence of RCC (HR = 1.618, P = 0.008). High AMC and ANC were significantly associated with reduced OS and PFS (P < 0.05), and ANC may be an independent prognostic factor. Public database analysis showed that signature genes of tumor-associated macrophages (TAMs) and tumor-associated neutrophils (TANs) were highly expressed in ccRCC. ConclusionsElevated preoperative ANC and AMC can distinguish RCC from RAML and predict poor prognosis in patients with RCC. Furthermore, the signature genes of TAMs and TANs exhibit high expression levels in clear cell RCC.

Major stress in early childhood strengthens the association between peripheral inflammatory activity and corticostriatal responsivity to reward

BackgroundSevere, chronic stress during childhood accentuates vulnerability to mental and physical health problems across the lifespan. To explain this phenomenon, the neuroimmune network hypothesis proposes that childhood stressors amplify signaling between peripheral inflammatory cells and developing brain circuits that support processing of rewards and threats. Here, we conducted a preliminary test of the basic premises of this hypothesis. Methods180 adolescents (mean age = 19.1 years; 68.9 % female) with diverse racial and ethnic identities (56.1 % White; 28.3 % Hispanic; 26.1 % Asian) participated. The Childhood Trauma Interview was administered to quantify early adversity. Five inflammatory biomarkers were assayed in antecubital blood — C-reactive protein, tumor necrosis factor-a, and interleukins-6, −8, and −10 — and were averaged to form a composite score. Participants also completed a functional MRI task to measure corticostriatal responsivity to the anticipation and acquisition of monetary rewards. ResultsStress exposure and corticostriatal responsivity interacted statistically to predict the inflammation composite. Among participants who experienced major stressors in the first decade of life, higher inflammatory activity covaried with lower corticostriatal responsivity during acquisition of monetary rewards. This relationship was specific to participants who experienced major stress in early childhood, implying a sensitive period for exposure, and were evident in both the orbitofrontal cortex and the ventral striatum, suggesting the broad involvement of corticostriatal regions. The findings were independent of participants’ age, sex, racial and ethnic identity, family income, and depressive symptoms. ConclusionsCollectively, the results are consistent with hypotheses suggesting that major stress in childhood alters brain-immune signaling.

Disease-specific corona mediated co-delivery of MTX and siRNA-TNFα by a polypeptide nanoplatform with antigen-scavenging functions in psoriasis

Psoriatic self-antigen LL37 has the ability to stimulate skin-homing T lymphocytes, which is the constitutive factor for the relapse of psoriasis. The local inflammatory modulation in psoriatic skin is not sufficient for the restoration of immune homeostasis. In this study, we found the expression levels of disease specific proteins including LL37, S100A8 and S100A9 were significantly increased in psoriasis. The self-assembled nanoparticles based on methoxy-poly(ethylene glycol)-block-poly(L-histidine) and methoxy-poly(ethylene glycol)-block-poly(L-lactic acid) (HLNPs) were capable of interacting and absorbing these disease specific proteins, leading to the accumulation of HLNPs in peripheral inflammatory immune cells. Therefore, we proposed an “Antigen-scavenging” polypeptide nano-system assembled from the “sandwich” structure composed of HLNPs, siRNA-TNFα, and oligolysine conjugated methotrexate prodrug (HLNP-MNs), with the encapsulation of ROS-responsive methotrexate prodrug and siRNA-TNFα. We evaluated the biological fate of HLNP-MNs in vivo, the ROS-responsive release of methotrexate (MTX) and siRNA-TNFα in inflammatory immune cells, the suppression of immune response triggered by autoantigen LL37 and the inhibition of skin-homing T lymphocytes from the aspects of “nanoparticle-protein” interaction, cellular level and mouse models. The design of “Antigen-scavenging” polypeptide nanoparticles with loading of MTX and siRNA-TNFα, can shed light on restoring immune homeostasis in psoriasis.

Rab Geranylgeranyltransferase Subunit Beta as a Potential Indicator to Assess the Progression of Amyotrophic Lateral Sclerosis.

Currently, there is no effective treatment for amyotrophic lateral sclerosis (ALS), a devastating neurodegenerative disorder. Many biomarkers have been proposed, but because ALS is a clinically heterogeneous disease with an unclear etiology, biomarker discovery for ALS has been challenging due to the lack of specificity of these biomarkers. In recent years, the role of autophagy in the development and treatment of ALS has become a research hotspot. In our previous studies, we found that the expression of RabGGTase (low RABGGTB expression and no change in RABGGTA) is lower in the lumbar and thoracic regions of spinal cord motoneurons in SOD1G93A mice compared with WT (wild-type) mice groups, and upregulation of RABGGTB promoted prenylation modification of Rab7, which promoted autophagy to protect neurons by degrading SOD1. Given that RabGGTase is associated with autophagy and autophagy is associated with inflammation, and based on the above findings, since peripheral blood mononuclear cells are readily available from patients with ALS, we proposed to investigate the expression of RabGGTase in peripheral inflammatory cells. Information and venous blood were collected from 86 patients diagnosed with ALS between January 2021 and August 2023. Flow cytometry was used to detect the expression of RABGGTB in monocytes from peripheral blood samples collected from patients with ALS and healthy controls. Extracted peripheral blood mononuclear cells (PBMCs) were differentiated in vitro into macrophages, and then the expression of RABGGTB was detected by immunofluorescence. RABGGTB levels in patients with ALS were analyzed to determine their impact on disease progression. Using flow cytometry in monocytes and immunofluorescence in macrophages, we found that RABGGTB expression in the ALS group was significantly higher than in the control group. Age, sex, original location, disease course, C-reactive protein (CRP), and interleukin-6 (IL-6) did not correlate with the ALS functional rating scale-revised (ALSFRS-R), whereas the RABGGTB level was significantly correlated with the ALSFRS-R. In addition, multivariate analysis revealed a significant correlation between RABGGTB and ALSFRS-R score. Further analysis revealed a significant correlation between RABGGTB expression levels and disease progression levels (ΔFS). The RABGGTB level was significantly increased in patients with ALS compared with healthy controls. An elevated RABGGTB level in patients with ALS is associated with the rate of progression in ALS, suggesting that elevated RABGGTB levels in patients with ALS may serve as an indicator for tracking ALS progression.

Galectin-3 promotes brain injury by modulating the phenotype of microglia via binding TLR-4 after intracerebral hemorrhage.

Intracerebral hemorrhage (ICH) is a stroke subtype with high mortality and disability rate, and neuroinflammation is involved in secondary brain injury. Galectin-3 (Gal-3) is one of the scaffold proteins of Galectins. Studies have indicated that Gal-3 plays an important role in the physiological and pathological state of the nervous system. Here we focus on the role of Gal-3 in ICH, especially in neuroinflammation. Injection of autologous blood into the right basal ganglia was used to simulate ICH injury, and the level of Gal-3 in brain was regulated by related means. The changes of Gal-3 were detected by western blot and immunofluorescence, the level of neuroinflammation by immunofluorescence staining and ELISA. Apoptosis and neuron loss were detected by TUNEL staining FJB staining and Nissl staining, and neurological deficits were judged by neurobehavioral tests. The protein level of Gal-3 increased at 24 h after ICH. Downregulation of Gal-3 level can reduce the infiltration of M1-type microglia and peripheral inflammatory cells, thus alleviating post-ICH neuroinflammation, and reducing cell apoptosis and neuron loss in brain tissue. ICH-induced neurological damage was rescued. Meanwhile, the promotion in the expression level of Gal-3 increased neuroinflammatory activation and nerve cell death, aggravating ICH-induced brain injury. This study proves that Gal-3 is involved in neuroinflammation and nerve damage after ICH. Gal-3 expression should not be encouraged early on to prevent neuroinflammation. which provides a new possibility for clinical treatment for ICH patients.

Polystyrene Microplastics Exacerbate Systemic Inflammation in High-Fat Diet-Induced Obesity.

Microplastics (MPs) are recognized as environmental pollutants with potential implications for human health. Considering the rapid increase in obesity rates despite stable caloric intake, there is a growing concern about the link between obesity and exposure to environmental pollutants, including MPs. In this study, we conducted a comprehensive investigation utilizing in silico, in vitro, and in vivo approaches to explore the brain distribution and physiological effects of MPs. Molecular docking simulations were performed to assess the binding affinity of three plastic polymers (ethylene, propylene, and styrene) to immune cells (macrophages, CD4+, and CD8+ lymphocytes). The results revealed that styrene exhibited the highest binding affinity for macrophages. Furthermore, in vitro experiments employing fluorescence-labeled PS-MPs (fPS-MPs) of 1 μm at various concentrations demonstrated a dose-dependent binding of fPS-MPs to BV2 murine microglial cells. Subsequent oral administration of fPS-MPs to high-fat diet-induced obese mice led to the co-existence of fPS-MPs with immune cells in the blood, exacerbating impaired glucose metabolism and insulin resistance and promoting systemic inflammation. Additionally, fPS-MPs were detected throughout the brain, with increased activation of microglia in the hypothalamus. These findings suggest that PS-MPs significantly contribute to the exacerbation of systemic inflammation in high-fat diet-induced obesity by activating peripheral and central inflammatory immune cells.

Recruitment of regulatory T cells with rCCL17 promotes M2 microglia/macrophage polarization through TGFβ/TGFβR/Smad2/3 pathway in a mouse model of intracerebral hemorrhage

AimsIntracerebral hemorrhage (ICH) is a severe neurological condition with high mortality and morbidity. Microglia activation and peripheral inflammatory cells infiltration play an important role in ICH prognosis. Previous studies demonstrated that regulatory T cells (Tregs) ameliorated neuroinflammation following experimental ICH. However, the molecular mechanism underlying such effects of Tregs remains unclear. The objective was to examine how Tregs recruitment induced by recombinant CC chemokine ligand 17 (rCCL17) influences microglia/macrophage polarization in an intrastriatal autologous blood injection ICH animal model, and to determine if TGFβ/TGFβ-R/Smad2/3 pathway was involved. Methods380 adult CD1 mice (male, eight weeks old) were subjected to sham surgery or autologous blood injection induced ICH. A CD25-specific mouse antibody or isotype control mAb was injected intraventricular (i.c.v) 48 h prior to ICH induction to deplete Tregs. rCCL17, a CC chemokine receptor 4 (CCR4) ligand, was delivered intranasally at 1 h post-ICH. SB431542, a specific inhibitor of TGF-β was administered intraperitoneally 1 h before ICH induction. Following the ICH, neurobehavioral testing, brain edema, hematoma volume, hemoglobin content, western blotting, double immunofluorescence labeling, and immunohistochemistry were performed. ResultsEndogenous expressions of CCL17, Tregs marker Foxp3, and the number of Tregs in perihematomal region increased following ICH. Tregs depletion with a CD25 antibody aggravated neurological deficits and brain edema, increased inflammatory cytokines, neutrophil infiltration, oxidative stress, and reduced the rate of hematoma resolution in ICH mice. rCCL17 treatment increased the number of Tregs in the brain, ameliorated neurological deficits and brain edema after ICH, and promoted microglia/macrophage polarization toward M2 phenotype which was reversed with CD25 antibody. Moreover, rCCL17 increased the expressions of brain TGF-β/phosphorylated-Smad2/3 which was abrogated with the selective TGFβ inhibitor SB431542. ConclusionsrCCL17-mediated Tregs recruitment may be a potential therapeutic strategy to promote M2 microglia/macrophages polarization and alleviate early brain injury following ICH.

GPR55 contributes to neutrophil recruitment and mechanical pain induction after spinal cord compression in mice

Pain transmission and processing in the nervous system are modulated by various biologically active substances, including lysophospholipids, through direct and indirect actions on the somatosensory pathway. Lysophosphatidylglucoside (LysoPtdGlc) was recently identified as a structurally unique lysophospholipid that exerts biological actions via the G protein-coupled receptor GPR55. Here, we demonstrated that GPR55-knockout (KO) mice show impaired induction of mechanical pain hypersensitivity in a model of spinal cord compression (SCC) without the same change in the models of peripheral tissue inflammation and peripheral nerve injury. Among these models, only SCC recruited peripheral inflammatory cells (neutrophils, monocytes/macrophages, and CD3+ T-cells) in the spinal dorsal horn (SDH), and GPR55-KO blunted these recruitments. Neutrophils were the first cells recruited to the SDH, and their depletion suppressed the induction of SCC-induced mechanical hypersensitivity and inflammatory responses in compressed SDH. Furthermore, we found that PtdGlc was present in the SDH and that intrathecal administration of an inhibitor of secretory phospholipase A2 (an enzyme required for producing LysoPtdGlc from PtdGlc) reduced neutrophil recruitment to compressed SDH and suppressed pain induction. Finally, by screening compounds from a chemical library, we identified auranofin as a clinically used drug with an inhibitory effect on mouse and human GPR55. Systemically administered auranofin to mice with SCC effectively suppressed spinal neutrophil infiltration and pain hypersensitivity. These results suggest that GPR55 signaling contributes to the induction of inflammatory responses and chronic pain after SCC via the recruitment of neutrophils and may provide a new target for reducing pain induction after spinal cord compression, such as spinal canal stenosis.

A mouse model and pathogenesis study for CVA19 first isolated from hand, foot, and mouth disease

ABSTRACT Coxsackievirus A19 (CVA19) is a member of Enterovirus (EV) C group in the Picornaviridae family. Recently, we reported a case of CVA19-infected hand, foot, and mouth disease (HFMD) for the first time. However, the current body of knowledge on the CVA19 infection, particularly the pathogenesis of encephalomyelitis and diarrhoea is still very limited, due to the lack of suitable animal models. Here, we successfully established a CVA19 mouse model via oral route based on 7-day-old ICR mice. Our results found the virus strain could directly infect the neurons, astrocytes of brain, and motor neurons of spinal cord causing neurological complications, such as acute flaccid paralysis. Importantly, viruses isolated from the spinal cords of infected mice caused severe illness in suckling mice, fulfilling Koch’s postulates to some extent. CVA19 infection led to diarrhoea with typical pathological features of shortened intestinal villi, increased number of secretory cells and apoptotic intestinal cells, and inflammatory cell infiltration. Much higher concentrations of serum cytokines and more peripheral blood inflammatory cells in CVA19-infected mice indicated a systematic inflammatory response induced by CVA19 infection. Finally, we found ribavirin and CVA19 VP1 monoclonal antibody could not prevent the disease progression, but higher concentrations of antisera and interferon alpha 2 (IFN-α2) could provide protective effects against CVA19. In conclusion, this study shows that a natural mouse-adapted CVA19 strain leads to diarrhoea and encephalomyelitis in a mouse model via oral infection, which provides a useful tool for studying CVA19 pathogenesis and evaluating the efficacy of vaccines and antivirals.

Biomarkers of Periodontitis and Its Differential DNA Methylation and Gene Expression in Immune Cells: A Systematic Review.

The characteristic epigenetic profile of periodontitis found in peripheral leukocytes denotes its impact on systemic immunity. In fact, this profile not only stands for periodontitis as a low-grade inflammatory disease with systemic effects but also as an important source of potentially valuable clinical biomarkers of its systemic effects and susceptibility to other inflammatory conditions. Thus, we aimed to identify relevant genes tested as epigenetic systemic biomarkers in patients with periodontitis, based on the DNA methylation patterns and RNA expression profiles in peripheral immune cells. A detailed protocol was designed following the Preferred Reporting Items for Systematic Review and Meta-analysis -PRISMA guideline. Only cross-sectional and case-control studies that reported potential systemic biomarkers of periodontitis in peripheral immune cell types were included. DNA methylation was analyzed in leukocytes, and gene expression was in polymorphonuclear and mononuclear cells. Hypermethylation was found in TLR regulators genes: MAP3K7, MYD88, IL6R, RIPK2, FADD, IRAK1BP1, and PPARA in early stages of periodontitis, while advanced stages presented hypomethylation of these genes. TGFB1I1, VNN1, HLADRB4, and CXCL8 genes were differentially expressed in lymphocytes and monocytes of subjects with poorly controlled diabetes mellitus, dyslipidemia, and periodontitis in comparison with controls. The DAB2 gene was differentially overexpressed in periodontitis and dyslipidemia. Peripheral blood neutrophils in periodontitis showed differential expression in 163 genes. Periodontitis showed an increase in ceruloplasmin gene expression in polymorphonuclears in comparison with controls. Several genes highlight the role of the epigenetics of peripheral inflammatory cells in periodontitis that could be explored in blood as a source of biomarkers for routine testing.

Abstract 5273: The peripheral proinflammatory responses in COVID-19: Clinical spectrum and outcome in patients with and without cancer

Abstract Background: A meta-analysis of COVID-19 shows that the pooled prevalence of cancer is 1.4%. Febrile illness during COVID-19 is caused by cytokine release syndrome energized by innate inflammatory immune cells, neutrophils, monocytes, and macrophages. Cancer has a worse clinical outcome with COVID-19 due to a potential contribution of the disordered inflammatory microenvironment and immune system. This study aimed to determine the impact of peripheral inflammatory responses on clinical outcome and severity of COVID-19 patients with and without cancer and compare their clinical spectra. Methodology: This IRB-approved, retrospective chart review performed at PNOC included patients 18 years or older with PCR-confirmed COVID-19 from April 2020 to April 2021. Histopathology-confirmed cases identified excluded cranial metastases, pregnancy, or ICU-ineligible due to advanced malignancy or missing data. We collected the first clinical encounter data following a positive COVID-19 test, including CDC-defined COVID-19 symptoms, co-morbidities, cancer status, and treatment—clinical outcomes and death from any cause within30 days of COVID-19 diagnosis. We determined peripheral blood inflammatory cells of neutrophils, lymphocytes, monocytes, platelets and the ratios between lymphocytes and the other three. According to INH guidelines, we ranked clinical severity as presymptomatic, mild, moderate, severe, or critical. Results: Of 3745 people with PCR-confirmed COVID-19, 65 (1.7%) had cancer. We randomly selected 130 non-cancer subjects, homogeneously distributed across each month. The median age was 59 years. Of all, 52.3% were women, 43% were diabetic, 45% were hypertensive, and 35% had the cardiopulmonary disease. Dyspnea occurs in 30.8% of those with cancer but in 59.2% of those without cancer (P &amp;lt; .001). High neutrophil was significantly associated with severity (P = .038), but there was no significant difference between cancer and non-cancer groups. High lymphocytes, MPV, and Neutrophil/Lymphocyte ratio were associated with symptoms but not outcome or severity. Death from any cause was more in the group with cancer 23.1% vs. 6.9%, P= .001. Only 2% of study participants with cancer continued chemotherapy after the diagnosis of COVID-19 was confirmed. Conclusion: Mortality significantly remains higher when cancer is comorbid with COVID-19, as seen in international groups. Further studies are needed to confirm whether cancer immunomodulation is a factor. Peripheral inflammatory response modestly predicts a worse outcome, particularly with elevated neutrophils, known for its proinflammatory rule by polarization and neutrophil extracellular trap (NET) formation with platelet activation. There was a modest increase in symptoms severity in non-cancer COVID19 but more mortality in cancer comorbid COVID-19 Citation Format: Amer N. Radwi, Zahra H. Alshardi, Rakan H. Alelyani, Raha M. Garout, Lojain N. Alruwaili, Muhammad T. Bakhsh. The peripheral proinflammatory responses in COVID-19: Clinical spectrum and outcome in patients with and without cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5273.

“Near Cure” treatment of severe acute EAE in MIF-1-deficient female and male mice with a bifunctional MHCII-derived molecular construct

Our previous studies demonstrated increased serum levels of macrophage migration inhibitory factor (MIF-1) and its homologue, MIF-2, in males during MS progression; and that genetically high-MIF-expressing male subjects with relapsing multiple sclerosis (MS) had a significantly greater risk of conversion to progressive MS than lower-MIF-expressing males and females. However, female MS subjects with severe disease expressed higher levels of CD74, the common MIF-1/MIF-2 receptor, on blood cells. In the murine model of MS, experimental autoimmune encephalomyelitis (EAE), both male and female mice lacking MIF-1 and/or MIF-2 were clinically improved during development of moderately severe disease, thus implicating both homologs as co-pathogenic contributors. The current study using MIF-deficient mice with severe acute EAE revealed a highly significant reduction of EAE scores in MIF-1-deficient females, in contrast to only minor and delayed reduction of clinical signs in MIF-1-deficient males. However, clinical EAE scores and factor expression were strongly suppressed in males and further reduced in females after treatment of WT and MIF-1-, MIF-2- and MIF-1/2-DUAL-deficient female and male mice with a MHCII DRα1-MOG-35-55 molecular construct that competitively inhibits MIF-1 & MIF-2 signaling through CD74 as well as T cell activation. These results suggest sex-dependent differences in which the absence of the MIF-1 and/or MIF-2 genotypes may permit stronger compensatory CD74-dependent EAE-inducing responses in males than in females. However, EAE severity in both sexes could still be reduced nearly to background (a “near cure”) with DRα1-MOG-35-55 blockade of compensatory MIF and CD74-dependent factors known to attract peripheral inflammatory cells into the spinal cord tissue.

Chromatin accessibility analysis reveals regulatory dynamics and therapeutic relevance of Vogt-Koyanagi-Harada disease

The barrier to curing Vogt–Koyanagi–Harada disease (VKH) is thought to reside in a lack of understanding in the roles and regulations of peripheral inflammatory immune cells. Here we perform a single-cell multi-omic study of 166,149 cells in peripheral blood mononuclear cells from patients with VKH, profile the chromatin accessibility and gene expression in the same blood samples, and uncover prominent cellular heterogeneity. Immune cells in VKH blood are highly activated and pro-inflammatory. Notably, we describe an enrichment of transcription targets for nuclear factor kappa B in conventional dendritic cells (cDCs) that governed inflammation. Integrative analysis of transcriptomic and chromatin maps shows that the RELA in cDCs is related to disease complications and poor prognosis. Ligand-receptor interaction pairs also identify cDC as an important predictor that regulated multiple immune subsets. Our results reveal epigenetic and transcriptional dynamics in auto-inflammation, especially the cDC subtype that might lead to therapeutic strategies in VKH.

Glycometabolism Reprogramming of Glial Cells in Central Nervous System: Novel Target for Neuropathic Pain.

Neuropathic pain is characterized by hyperalgesia and allodynia. Inflammatory response is conducive to tissue recovery upon nerve injury, but persistent and exaggerated inflammation is detrimental and participates in neuropathic pain. Synaptic transmission in the nociceptive pathway, and particularly the balance between facilitation and inhibition, could be affected by inflammation, which in turn is regulated by glial cells. Importantly, glycometabolism exerts a vital role in the inflammatory process. Glycometabolism reprogramming of inflammatory cells in neuropathic pain is characterized by impaired oxidative phosphorylation in mitochondria and enhanced glycolysis. These changes induce phenotypic transition of inflammatory cells to promote neural inflammation and oxidative stress in peripheral and central nervous system. Accumulation of lactate in synaptic microenvironment also contributes to synaptic remodeling and central sensitization. Previous studies mainly focused on the glycometabolism reprogramming in peripheral inflammatory cells such as macrophage or lymphocyte, little attention was paid to the regulation effects of glycometabolism reprogramming on the inflammatory responses in glial cells. This review summarizes the evidences for glycometabolism reprogramming in peripheral inflammatory cells, and presents a small quantity of present studies on glycometabolism in glial cells, expecting to promote the exploration in glycometabolism in glial cells of neuropathic pain.

Betanin Dose-Dependently Ameliorates Allergic Airway Inflammation by Attenuating Th2 Response and Upregulating cAMP-PKA-CREB Pathway in Asthmatic Mice.

Allergic asthma is a refractory disease that affects hundreds of millions of people worldwide. Betanin is a natural plant-derived nutrient and possesses health-promoting properties. The effects of betanin on allergic asthma remain unknown. Herein, the effects and mechanisms of betanin on allergic asthma were explored in ovalbumin (OVA)-induced BALB/c mice. Betanin in doses of 0, 20, 60, and 180 mg/kg was applied. Peripheral inflammatory cells, IgE, pulmonary pathology, T cell subsets, cytokine levels, protein expressions of the cAMP-PKA-CREB/CREM pathway, and gut microbial profile were measured. The 60 and 180 mg/kg/day betanin doses significantly downregulated IgE, eotaxin, eosinophil infiltration, mucus hyperproduction, and Th2. A 180 mg/kg/day betanin dose also significantly reduced percentages of Th17, Tc17, and Tc2 and Th2- and Th17-signature cytokines and upregulated the cAMP-PKA-CREB pathway. Additionally, 20 mg/kg/day betanin altered the gut microbial profile. In conclusion, betanin dose-dependently alleviated allergic asthma and upregulated the cAMP-PKA-CREB pathway in mice. This study provides a novel nutritional strategy to treat allergic asthma.

Decreased Astrocytic CCL2 Accounts for BAF-312 Effect on PBMCs Transendothelial Migration Through a Blood Brain Barrier in Vitro Model

Disruption of the blood brain barrier (BBB) is a common event in several neurological diseases and in particular, in multiple sclerosis (MS), it contributes to the infiltration of the central nervous system by peripheral inflammatory cells. Sphingosine-1-phosphate (S1P) is a bioactive molecule with pleiotropic effects. Agonists of S1P receptors such as fingolimod and siponimod (BAF-312) are in clinical practice for MS and have been shown to preserve BBB function in inflammatory conditions. Using an in vitro BBB model of endothelial-astrocytes co-culture exposed to an inflammatory insult (tumor necrosis factor-α and interferon-γ; T&I), we show that BAF-312 reduced the migration of peripheral blood mononuclear cells (PBMCs) through the endothelial layer, only in the presence of astrocytes. This effect was accompanied by decreased expression of the adhesion molecule ICAM-1. BAF-312 also reduced the activation of astrocytes, by controlling NF-kB and NLRP3 induction and preventing the increase of proinflammatory cytokine and chemokines. Reduction of CCL2 by BAF-312 may be responsible for the observed effects and, accordingly, addition of exogenous CCL2 was able to counteract BAF-312 effects and rescued T&I responses on PBMC migration, ICAM-1 expression and astrocyte activation. The present results further point out BAF-312 effects on BBB properties, suggesting also the key role of astrocytes in mediating drug effects on endothelial function.Graphical abstract

Ablation of lysozyme M-positive cells prevents aircraft noise-induced vascular damage without improving cerebral side effects

Aircraft noise induces vascular and cerebral inflammation and oxidative stress causing hypertension and cardiovascular/cerebral dysfunction. With the present studies, we sought to determine the role of myeloid cells in the vascular vs. cerebral consequences of exposure to aircraft noise. Toxin-mediated ablation of lysozyme M+ (LysM+) myeloid cells was performed in LysMCreiDTR mice carrying a cre-inducible diphtheria toxin receptor. In the last 4d of toxin treatment, the animals were exposed to noise at maximum and mean sound pressure levels of 85 and 72 dB(A), respectively. Flow cytometry analysis revealed accumulation of CD45+, CD11b+, F4/80+, and Ly6G−Ly6C+ cells in the aortas of noise-exposed mice, which was prevented by LysM+ cell ablation in the periphery, whereas brain infiltrates were even exacerbated upon ablation. Aircraft noise-induced increases in blood pressure and endothelial dysfunction of the aorta and retinal/mesenteric arterioles were almost completely normalized by ablation. Correspondingly, reactive oxygen species in the aorta, heart, and retinal/mesenteric vessels were attenuated in ablated noise-exposed mice, while microglial activation and abundance in the brain was greatly increased. Expression of phagocytic NADPH oxidase (NOX-2) and vascular cell adhesion molecule-1 (VCAM-1) mRNA in the aorta was reduced, while NFκB signaling appeared to be activated in the brain upon ablation. In sum, we show dissociation of cerebral and peripheral inflammatory reactions in response to aircraft noise after LysM+ cell ablation, wherein peripheral myeloid inflammatory cells represent a dominant part of the pathomechanism for noise stress-induced cardiovascular effects and their central nervous counterparts, microglia, as key mediators in stress responses.

The role of peripheral inflammatory cells in predicting radiation pneumonitis

The role of peripheral inflammatory cells in predicting radiation pneumonitis

The role of peripheral inflammatory cells in predicting radiation pneumonitis

The role of peripheral inflammatory cells in predicting radiation pneumonitis