Proinflammatory Chemokines Research Articles

Biobehavioral mechanisms underlying symptoms in cancer patients with chronic graft-versus-host disease

Chronic graft-versus-host disease (cGVHD) is a complication of allogeneic hematopoietic cell transplant (HCT) and is associated with morbidity and high symptom burden. This study evaluated two biobehavioral mechanisms, inflammation and circadian rest-activity rhythms, that may underly commonly reported psychological and physical symptoms in cGVHD patients. Adults with cGVHD (N=57) wore a wrist actigraph for 7 days, provided a blood sample, and completed patient-reported outcome (PRO) measures. 24-hour rest-activity indices were derived from actigraphy. Cytokines and chemokines relevant to cGVHD were measured in peripheral blood plasma using multi-analyte immunoassays. Multiple regression evaluated the extent to which rest-activity indices and inflammatory biomarkers predicted PROs. Higher levels of circulating IL-8 and MIP-1α were associated with worse depression (β = 0.35, p = 0.01; β = 0.33, p = 0.02) and sexual function (β = -0.41, p = 0.01; β = -0.32, p = 0.03). MIP-1α was associated with more severe insomnia (β = 0.36, p = 0.01). Higher circulating MIF was associated with more severe anxiety (β = 0.28, p = 0.048) and fatigue (β = 0.35, p = 0.02). Il-6, TNFα, and MCP-1 showed few associations with PROs. There were few associations between actigraphy indices and PROs; however, participants with a later daily activity peak (acrophase) reported poorer sexual function (β = -0.31, p = 0.04). Models covarying for age, cGVHD severity, and time since HCT yielded a similar pattern of results. Results suggest that pro-inflammatory cytokines and chemokines associated with cGVHD may contribute to PROs, identifying a biobehavioral mechanism that may be a useful target for future interventions.

The angiotensin-(1-7)/MasR axis improves pneumonia caused by Pseudomonas aeruginosa: Extending the therapeutic window for antibiotic therapy.

Pseudomonas aeruginosa is a frequent cause of antimicrobial-resistant hospital-acquired pneumonia, especially in critically ill patients. Inflammation triggered by P. aeruginosa infection is necessary for bacterial clearance but must be spatially and temporally regulated to prevent further tissue damage and bacterial dissemination. Emerging data have shed light on the pro-resolving actions of angiotensin-(1-7) [Ang-(1-7)] signaling through the G protein-coupled receptor Mas (MasR) during infections. Herein, we investigated the role of the Ang-(1-7)/Mas axis in pneumonia caused by P. aeruginosa by using genetic and pharmacological approach and found that Mas receptor-deficient animals developed a more severe form of pneumonia showing higher neutrophilic infiltration into the airways, bacterial load, cytokines, and chemokines production and more severe pulmonary damage. Conversely, treatment of pseudomonas-infected mice with Ang-(1-7) was able to decrease neutrophilic infiltration in airways and lungs, local and systemic levels of pro-inflammatory cytokines and chemokines, and increase the efferocytosis rates, mitigating lung damage/dysfunction caused by infection. Notably, the therapeutic association of Ang-(1-7) with antibiotics improved the survival rates of mice subjected to lethal inoculum of P. aeruginosa, extending the therapeutic window for imipenem. Mechanistically, Ang-(1-7) increased phagocytosis of bacteria by neutrophils and macrophages to accelerate pathogen clearance. Altogether, harnessing the Ang-(1-7) pathway during infection is a potential strategy for the development of host-directed therapies to promote mechanisms of resistance and resilience to pneumonia.

Therapeutic Correlation of TLR-4 Mediated NF-κB Inflammatory Pathways in Ischemic Injuries.

Ischemia-reperfusion (I/R) injury refers to the tissue damage that happens when blood flow returns to tissue after a period of ischemia. I/R injuries are implicated in a large array of pathological conditions, such as cerebral, myocardial, renal, intestinal, retinal and hepatic ischemia. The hallmark of these pathologies is excessive inflammation. Toll-like receptors (TLRs) are recognized as significant contributors to inflammation caused by pathogens and, more recently, inflammation caused by injury. TLR-4 activation initiates a series of events that results in activation of nuclear factor kappa-B (NF-κB), which stimulates the production of pro-inflammatory cytokines and chemokines, exacerbating tissue injury. Therefore, through a comprehensive review of current research and experimentation, this investigation elucidates the TLRs signalling pathway and the role of TLR-4/NF-κB in the pathophysiology of I/R injuries. Furthermore, this review highlights the various pharmacological agents (TLR-4/NF-κB inhibitors) with special emphasis on the various ischemic injuries (cerebral, myocardial, renal, intestinal, retinal and hepatic). Future research should prioritise investigating the specific molecular pathways that cause TLR-4/NF-κBmediated inflammation in ischemic injuries. Additionally, efforts should be made to enhance treatment approaches in order to enhance patient outcomes.

Neutrophil extracellular traps promote M1 macrophage polarization in gouty inflammation via targeting hexokinase-2

Peptidylarginine deiminase 4 (PAD4)-dependent neutrophil extracellular trap (NET) formation is a new neutrophil death mechanism. Increased NET formation has been demonstrated to be associated with gouty inflammation. Macrophages release proinflammatory mediators and chemokines in acute gouty inflammation and subsequently lead to inflammatory cascades. However, whether NETs regulate macrophage function and polarization and further contribute to gout development remains unclear. Herein, we investigated the relationship between monosodium urate (MSU) crystal-induced NETs and macrophages and the associated mechanisms in gouty inflammation. Elevated NET formation and CD86+ macrophage infiltration were observed in human gouty arthritis (GA). In vitro, MSU crystal-induced NETs or NET-associated histone H3 treatments modulated nod-like receptor protein 3 (NLRP3) inflammasome activation, M1 polarization, and metabolic changes in macrophages. These effects were eliminated by hexokinase-2 (HK-2) silencing. Moreover, NET formation and inflammation were significantly reduced in PAD4−/− GA mice. Pharmacological inhibition of NET formation with Cl-Amidine or NET degradation with DNase Ⅰ significantly reduced M1 polarization of macrophages and ameliorated inflammation in GA mice. In sum, MSU crystal-induced NETs promote M1 polarization and NLRP3 activation in macrophages via targeting HK-2. Cell-free DNA and histone H3 may be the driving elements behind the NET-induced M1 macrophage polarization, NLRP3 activation, and metabolic changes. Targeting NETs could be a potential therapeutic strategy for gout flare.

Tipping-point transition from transient to persistent inflammation in pancreatic islets

Type 2 diabetes (T2D) is associated with a systemic increase in the pro-inflammatory cytokine IL-1β. While transient exposure to low IL-1β concentrations improves insulin secretion and β-cell proliferation in pancreatic islets, prolonged exposure leads to impaired insulin secretion and collective β-cell death. IL-1 is secreted locally by islet-resident macrophages and β-cells; however, it is unknown if and how the two opposing modes may emerge at single islet level. We investigated the duality of IL-1β with a quantitative in silico model of the IL-1 regulatory network in pancreatic islets. We find that the network can produce either transient or persistent IL-1 responses when induced by pro-inflammatory and metabolic cues. This suggests that the duality of IL-1 may be regulated at the single islet level. We use two core feedbacks in the IL-1 regulation to explain both modes: First, a fast positive feedback in which IL-1 induces its own production through the IL-1R/IKK/NF-κB pathway. Second, a slow negative feedback where NF-κB upregulates inhibitors acting at different levels along the IL-1R/IKK/NF-κB pathway—IL-1 receptor antagonist and A20, among others. A transient response ensues when the two feedbacks are balanced. When the positive feedback dominates over the negative, islets transit into the persistent inflammation mode. Consistent with several observations, where the size of islets was implicated in its inflammatory state, we find that large islets and islets with high density of IL-1β amplifying cells are more prone to transit into persistent IL-1β mode. Our results are likely not limited to IL-1β but are general for the combined effect of multiple pro-inflammatory cytokines and chemokines. Generalizing complex regulations in terms of two feedback mechanisms of opposing nature and acting on different time scales provides a number of testable predictions. Taking islet architecture and cellular heterogeneity into consideration, further dynamic monitoring and experimental validation in actual islet samples will be crucial to verify the model predictions and enhance its utility in clinical applications.

Design and Optimization of Selectivity-Tunable Toll-like Receptor 7/8 Agonists as Novel Antibody-Drug Conjugate Payloads.

Toll-like receptors 7 and 8 are involved in modulating the adaptive and innate immune responses, and their activation has shown promise as a therapeutic strategy in the field of immuno-oncology. While systemic exposure to TLR7/8 agonists can result in poor tolerance, combination therapies and targeted delivery through antibody-drug conjugates (ADCs) can help mitigate adverse effects. Described herein is the identification of a novel and potent series of pyrazolopyrimidine-based TLR7/8 agonists with tunable receptor selectivity. Representative agonists from this series were successfully able to induce the production of various proinflammatory cytokines and chemokines from human peripheral blood mononuclear cells. Anti-HER2-25 and anti-HER2-26 ADCs made from this class of payloads demonstrated mechanism-based activation of TLR7/8 in a THP1/N87 coculture system.

Microplastics caused embryonic growth retardation and placental dysfunction in pregnant mice by activating GRP78/IRE1α/JNK axis induced apoptosis and endoplasmic reticulum stress

Microplastics (MPs), a brand-new class of worldwide environmental pollutant, have received a lot of attention. MPs are consumed by both humans and animals through water, food chain and other ways, which may cause potential health risks. However, the effects of MPs on embryonic development, especially placental function, and its related mechanisms still need to be further studied. We investigated the impact on fetal development and placental physiological function of pregnant mice by consecutive gavages of MPs at 0, 25, 50, 100 mg/kg body weight during gestational days (GDs 0–14). The results showed that continuous exposure to high concentrations of MP significantly reduced daily weight gain and impaired reproductive performance of pregnant mice. In addition, MPs could significantly induce oxidative stress and placental dysfunction in pregnant mice. On the other hand, MPs exposure significantly decreased placental barrier function and induced placental inflammation. Specifically, MPs treatment significantly reduced the expression of tight junction proteins in placentas, accompanied by inflammatory cell infiltration and increased mRNA levels of pro-inflammatory cytokines and chemokines in placentas. Finally, we found that MPs induced placental apoptosis and endoplasmic reticulum (ER) stress through the GRP78/IRE1α/JNK axis, leading to placental dysfunction and decreased reproductive performance in pregnant mice. We revealed for the first time that the effects of MPs on placental dysfunction in pregnant animals. Blocking the targets of MPs mediated ER stress will provide potential therapeutic ideas for the toxic effects of MPs on maternal pregnancy.

Sodium butyrate alleviates lipopolysaccharide-induced inflammation through JAK/STAT signalling in primary human corneal fibroblasts

BackgroundBacterial keratitis is a common cause of blindness. Antibiotic treatment leads to the rapid release of lipopolysaccharide (LPS), which can activate corneal fibroblasts and cause persistent and excessive inflammatory responses. The anti-inflammatory drugs currently used to treat keratitis have serious side effects. Therefore, the ability of sodium butyrate (NaB), which can suppress the production of proinflammatory cytokines and promote the production of anti-inflammatory cytokines, to ameliorate keratitis was assessed in the present study. MethodsThe effect of NaB on the viability of primary human corneal fibroblasts was assayed with a CCK-8 kit. Cell migration was assessed by an in vitro scratch assay. Cell phenotypes were assessed by Western blotting and immunofluorescence staining. An antibody array was used to measure the production of proinflammatory cytokines and chemokines. ResultsAt 0–1 mM, NaB had no significant effect on cell viability, promoted the expression of the keratocyte marker keratocan and inhibited the fibroblast marker vimentin. Inhibition of cell migration was observed in the wound healing assay. By targeting the Janus kinase/signal transducer and activator of transcription (JAK/STAT) signalling pathway, NaB decreased the levels of inflammation-related cytokines and chemokines whose expression was induced by LPS. ConclusionsNaB maintained the keratocyte phenotype, inhibited cell migration, and relieved LPS-induced inflammatory responses through the JAK/STAT signalling pathway.

Epidermal Growth Factor Receptor Signaling Governs the Host Inflammatory Response to Invasive Aspergillosis.

The epidermal growth factor receptor (EGFR) has been identified as an epithelial cell receptor for Mucorales fungi and Candida albicans. Blocking EGFR with small molecule inhibitors reduces disease severity in mouse models of mucormycosis and oropharyngeal candidiasis. In contrast, cases of invasive aspergillosis have been reported in cancer patients who were treated with EGFR inhibitors, suggesting that EGFR signaling may play a protective role in the host defense against this infection. Here, we analyzed transcriptomic data from the lungs of mice with invasive aspergillosis and found evidence that Aspergillus fumigatus infection activates multiple genes that are predicted to function in the EGFR signaling pathway. We also found that A. fumigatus infection activates EGFR in both a human small airway epithelial (HSAE) cell line and in the lungs of immunosuppressed mice. EGFR signaling in HSAE cells is required for maximal endocytosis of A. fumigatus and for fungal-induced proinflammatory cytokine and chemokine production. In a corticosteroid immunosuppressed mouse model of invasive pulmonary aspergillosis, inhibition of EGFR with gefitinib decreased whole lung chemokine levels and reduced accumulation of phagocytes in the lung, leading to a decrease in fungal killing, an increase in pulmonary fungal burden, and accelerated mortality. Thus, EGFR signaling is required for pulmonary epithelial cells to orchestrate the host innate immune defense against invasive aspergillosis in immunosuppressed hosts.

PHGDH/SYK: a hub integrating anti-fungal immunity and serine metabolism.

Immune cells modify their metabolic pathways in response to fungal infections. Nevertheless, the biochemical underpinnings need to be better understood. This study reports that fungal infection drives a switch from glycolysis to the serine synthesis pathway (SSP) and one-carbon metabolism by inducing the interaction of spleen tyrosine kinase (SYK) and phosphoglycerate dehydrogenase (PHGDH). As a result, PHGDH promotes SYK phosphorylation, leading to the recruitment of SYK to C-type lectin receptors (CLRs). The CLR/SYK complex initiates signaling cascades that lead to transcription factor activation and pro-inflammatory cytokine production. SYK activates SSP and one-carbon metabolism by inducing PHGDH activity. Then, one-carbon metabolism supports S-adenosylmethionine and histone H3 lysine 36 trimethylation to drive the production of pro-inflammatory cytokines and chemokines. These findings reveal the crosstalk between amino acid metabolism, epigenetic modification, and CLR signaling during fungal infection.

Vaginal Bacteria and Proinflammatory Host Immune Mediators as Biomarkers of Human Immunodeficiency Virus Acquisition Risk Among African Women.

Few investigations have assessed contributions of both vaginal bacteria and proinflammatory immune mediators to human immunodeficiency virus (HIV) acquisition risk in a prospective cohort. We conducted a nested case-control study of African women who participated in a randomized placebo-controlled trial of daily oral versus vaginal tenofovir-based preexposure prophylaxis for HIV infection. Vaginal concentrations of 23 bacterial taxa and 16 immune mediators were measured. Relationships between individual bacterial concentrations or immune mediators and HIV risk were analyzed using generalized estimating equations in a multivariable model. Factor analysis assessed relationships between combinations of bacterial taxa, immune mediators, and HIV acquisition risk. We identified 177 HIV pre-seroconversion visits from 150 women who acquired HIV and 531 visits from 436 women who remained HIV uninfected. Fourteen bacterial taxa and 6 proinflammatory cytokines and chemokines were individually associated with greater HIV risk after adjusting for confounders. Women with all 14 taxa versus <14 taxa (adjusted odds ratio [aOR], 4.45 [95% confidence interval {CI}, 2.20-8.98]; P < .001) or all 6 immune mediators versus <6 mediators (aOR, 1.77 [95% CI, 1.24-2.52]; P < .001) had greater risk for HIV acquisition. Factor analysis demonstrated that a bacterial factor comprised of 14 high-risk bacterial taxa (aOR, 1.57 [95% CI, 1.27-1.93]; P < 0.001) and the interferon gamma-induced protein 10 (highest quartile: aOR, 3.19 [95% CI, 1.32-7.72]; P = 0.002) contributed to the highest HIV risk. Bacterial and host biomarkers for predicting HIV acquisition risk identify women at greatest risk for HIV infection and can focus prevention efforts.

On the issue of the syndromic forms of pyoderma gangrenosum

Gangrenous pyoderma (PG) is an autoinflammatory polygenic neutrophilic dermatosis characterized by the formation of painful ulcerative skin defects with boldly raised undercut edges of purplish-cyanotic coloration and an erythema zone around the focus. Gangrenous pyoderma can manifest as an isolated dermatosis, and be associated with various autoinflammatory syndromes: PASH (gangrenous pyoderma, conglobate acne and purulent hydradenitis), PAPA (gangrenous pyoderma, pyogenic arthritis and conglobate acne), PAPASH (gangrenous pyoderma, pyogenic arthritis, conglobate acne and purulent hydradenitis), PAPASC (gangrenous pyoderma, pyogenic arthritis, conglobate acne, purulent hydradenitis and ulcerative colitis), etc. A number of genetic mutations have been found in the syndromic forms of gangrenous pyoderma (MEFV, NOD2, LPIN2, NLRP3, NLRP12, PSMB8, MVK, IL1RN, PSTPIP1) affecting inflammatory regulatory proteins, which contributes to the development of an autoaggressive process. Neutrophilic autoinflammatory syndromes have a common pathogenesis mechanism, which is an excessive activation of the innate link of the immune system, with hyperproduction of proinflammatory IL-1, IL-17 and chemokines, leading to aseptic neutrophilic inflammation of the skin. At the moment, the treatment of syndromic conditions remains a difficult task. Systemic glucocorticosteroids, immunosuppressants, antimetabolites, and sulfone preparations are used in complex therapy, however, more and more studies indicate the possibility of therapy with genetically engineered biological drugs with TNF inhibitors, IL-1 and IL-17. We present two clinical observations of rare forms of autoinflammatory neutrophilic syndromic conditions PASH and PAPASC in patients aged 20 and 21 years

Immunocellular microenvironment of the vascular wall of cerebral aneurysms: What is the role of inflammatory cells in aneurysmal remodeling?

AbstractIntracranial aneurysms (IAs) may afflict up to 5% of the general population, or up to 15 million individuals in the US. The two forms of IAs that can be recognized by their shape are saccular and nonsaccular IAs, with uncommon aneurysm types, fusiform and dissecting aneurysms, comprising 13% of nonsaccular IAs. Conceivably, among the various risk factors for IA development, vessel wall inflammation represents a major cause. Accordingly, IAs may not necessarily be the result of passive widening of vessel wall structures, but may also be the result of inflammation and tissue degeneration. Thus, flow‐induced vascular remodeling during IA pathogenesis may reflect immune cell infiltration and consequent release of proinflammatory cytokine, chemokine, and matrix metalloproteinase that contribute to vessel wall degeneration and weakening. Thus, infiltrating neutrophils, macrophages, T‐lymphocytes and complement factors, and the resulting immune microenvironment may be pertinent in IA pathogenesis.

Olfr2-positive macrophages originate from monocytes proliferate in situ and present a pro-inflammatory foamy-like phenotype.

Olfactory receptor 2 (Olfr2) has been identified in a minimum of 30% of vascular macrophages, and its depletion was shown to reduce atherosclerosis progression. Mononuclear phagocytes, including monocytes and macrophages within the vessel wall, are major players in atherosclerosis. Single-cell RNA sequencing studies revealed that atherosclerotic artery walls encompass several monocytes and vascular macrophages, defining at least nine distinct subsets potentially serving diverse functions in disease progression. This study investigates the functional phenotype and ontogeny of Olfr2-expressing vascular macrophages in atherosclerosis. Olfr2+ macrophages rapidly increase in Apoe-/- mice's aorta when fed a Western diet (WD). Mass cytometry showed that Olfr2+ cells are clustered within the CD64 high population and enriched for CD11c and Ccr2 markers. Olfr2+ macrophages express many pro-inflammatory cytokines, including Il1b, Il6, Il12, and Il23, and chemokines, including Ccl5, Cx3cl1, Cxcl9, and Ccl22. By extracting differentially expressed genes from bulk RNA sequencing (RNA-seq) of Olfr2+ vs. Olfr2- macrophages, we defined a signature that significantly mapped to single-cell data of plaque myeloid cells, including monocytes, subendothelial MacAir, and Trem2Gpnmb foamy macrophages. By adoptive transfer experiments, we identified that Olfr2 competent monocytes from CD45.1Apoe-/-Olfr2+/+ mice transferred into CD45.2Apoe-/-Olfr2-/- recipient mice fed WD for 12 weeks, accumulate in the atherosclerotic aorta wall already at 72 h, and differentiate in macrophages. Olfr2+ macrophages showed significantly increased BrdU incorporation compared to Olfr2- macrophages. Flow cytometry confirmed that at least 50% of aortic Olfr2+ macrophages are positive for BODIPY staining and have increased expression of both tumour necrosis factor and interleukin 6 compared to Olfr2- macrophages. Gene set enrichment analysis of the Olfr2+ macrophage signature revealed a similar enrichment pattern in human atherosclerotic plaques, particularly within foamy/TREM2hi-Mφ and monocytes. In summary, we conclude that Olfr2+ macrophages in the aorta originate from monocytes and can accumulate at the early stages of disease progression. These cells can undergo differentiation into MacAir and Trem2Gpnmb foamy macrophages, exhibiting proliferative and pro-inflammatory potentials. This dynamic behaviour positions them as key influencers in shaping the myeloid landscape within the atherosclerotic plaque.

YjbH contributes to Staphylococcus aureus skin pathology and immune response through Agr-mediated α-toxin regulation

ABSTRACT Staphylococcus aureus is the most common cause of skin and soft tissue infections (SSTIs) with Methicillin-Resistant S. aureus (MRSA) strains being a major contributor in both community and hospital settings. S. aureus relies on metabolic diversity and a large repertoire of virulence factors to cause disease. This includes α-hemolysin (Hla), an integral player in tissue damage found in various models, including SSTIs. Previously, we identified a role for the Spx adapter protein, YjbH, in the regulation of several virulence factors and as an inhibitor of pathogenesis in a sepsis model. In this study, we found that YjbH is critical for tissue damage during SSTI, and its absence leads to decreased proinflammatory chemokines and cytokines in the skin. We identified no contribution of YjbI, encoded on the same transcript as YjbH. Using a combination of reporters and quantitative hemolysis assays, we demonstrated that YjbH impacts Hla expression and activity both in vitro and in vivo. Additionally, expression of Hla from a non-native promoter reversed the tissue damage phenotype of the ΔyjbIH mutant. Lastly, we identified reduced Agr activity as the likely cause for reduced Hla production in the ΔyjbH mutant. This work continues to define the importance of YjbH in the pathogenesis of S. aureus infection as well as identify a new pathway important for Hla production.

Gynostemma pentaphyllum saponins shield mice from peanut allergy by modulation of gut microbiota: A novel approach for peanut allergy management

BackgroundFood allergies, particularly peanut (PN) allergies, are a growing concern, with fatal anaphylaxis incidents often reported. While palforzia is the sole FDA-approved drug for managing PN allergies, it is not universally effective. PurposeThis study aimed to investigate the potential of Gynostemma pentaphyllum saponins (GpS) as a novel therapeutic agent for PN allergy through modulation of gut microbiota, addressing the limitations of current treatments. MethodsTo elucidate the role of GpS on peanut allergy, we first built a PN-sensitized C57BL/6J model mice. Through comprehensive sequencing analysis, we identified Parabacteroides distasonis as a key bacterium triggering PN sensitization. Employing the same mouse model, GpS was evaluated for its effects on anaphylactic symptoms, serum immunoglobulin levels, and allergy-related biomarkers. 16S rRNA sequencing and transcriptomic analysis were applied to investigate the impact of GpS on the host's gut epithelium and microbiome. ResultsGpS treatment effectively reduced anaphylactic symptoms in PN-sensitized mice, as shown by decreased IgG1, total IgE, and PN-specific IgE levels. It also modulated the immune response by suppressing proinflammatory cytokines (IL-1β, IFN-γ, IL-21) and chemokines (CCL5, CCL12, CCL17, CCL22), while enhancing anti-inflammatory cytokines (IL-4, IL-10, IL-12, IL-13). Fecal microbial transplant from GpS-treated Model mice to PN-sensitized mice displayed anti-peanut allergy effects. Additionally, the administration of GpS-enhanced bacteria (Clostridium aldenese or Lactobacillus murinus), alleviated anaphylactic symptoms and reduced serum allergy markers in PN-sensitized mice. ConclusionTo conclude, we revealed the intestinal environment, signaling molecules, mucosal cytokines, and commensal microbial profiles in the peanut-sensitized mouse model. We further presented evidence for the protective effect of GpS against PN allergen sensitization by downregulating a series of food-allergy-associated biomarkers and cytokines via the modulation of gut bacteria. More importantly, supported by both in vitro and in vivo experiments, we demonstrated that the protective effect of GpS against PN-allergy is through the enhancement of two commensal bacteria, Clostridium aldenese, and Lactobacillus murinus.

Abstract P159: Conditional deletion of ADAM17 (A disintegrin and metalloprotease 17) in microglia attenuates hypertension and associated inflammation.

Microglia, the resident immune cell in the brain, contributes to neuroinflammation and neurogenic hypertension by secreting various cytokines and chemokines. ADAM17 shedding of these signaling molecules) in microglia modulates synaptic function but the consequences of this process have not been studied in neurogenic hypertension. Accordingly, we hypothesize that deletion of ADAM17 in microglia opposes microglia activation and cytokine secretion thus preventing the development of neuroinflammation in salt-sensitive hypertension. To test our hypothesis, a new mouse model (ADAM17::CX3CR1-CreERT2; A17-Mic-/-) amenable for selective deletion of ADAM17 in microglia was developed. Following the initiation of deoxycorticosterone acetate plus salt (DOCA-salt) hypertension, tamoxifen was injected intracerebroventricularly to delete ADAM17 in microglia and blood pressure (BP) monitored over 3 weeks. In A17-Mic-/- mice, lacking ADAM17 in microglia, the BP increase induced by DOCA-salt treatment was blunted compared to control mice (127.4±5 vs. 143.4±4 mmHg, P&lt;0.05). However, it was not abated in iRhom2-/- mice (149.5±3 mmHg), lacking the rhomboid protein involved in ADAM17 maturation in microglia, suggesting possible compensation by iRhom1. Interestingly, A17-Mic-/- mice showed a reduced level of proinflammatory cytokines and chemokines in the plasma, including TNF-α (A17-Mic-/-: 5.21±0.97, iRhom2-/-: 3.867±1 vs. control: 20.72±4 pg/mL), IL-6 (A17-Mic-/-: 36.53±11.33, iRhom2-/-: 91.41±14 vs. control: 79.65±15.72 pg/mL) and G-CSF (A17-Mic-/-: 508.4±98.7, iRhom2-/-: 3523±897 vs. 838.2±238.2 pg/mL) and MCP-1 (A17-Mic-/-: 38.41±9, iRhom2-/-: 51.87±7 vs. control: 75.52±12 pg/mL), respectively (P&lt;0.05). Together, our data suggests that conditional deletion of ADAM17 opposes the activation of microglia and reduces pro-inflammatory cytokine and chemokine expression in hypertension. Overall, our data highlights the pivotal role of microglial ADAM17 in regulating salt-sensitive hypertension and the associated inflammation.

Neutrophil estimation and prognosis analysis based on existing lung squamous cell carcinoma datasets: the development and validation of a prognosis prediction model.

Notwithstanding the rapid developments in precision medicine in recent years, lung cancer still has a low survival rate, especially lung squamous cell cancer (LUSC). The tumor microenvironment (TME) plays an important role in the progression of lung cancer, in which high neutrophil levels are correlated with poor prognosis, potentially due to their interactions with tumor cells via pro-inflammatory cytokines and chemokines. However, the precise mechanisms of how neutrophils influence lung cancer remain unclear. This study aims to explore these mechanisms and develop a prognosis predictive model in LUSC, addressing the knowledge gap in neutrophil-related cancer pathogenesis. LUSC datasets from the Xena Hub and Gene Expression Omnibus (GEO) databases were used, comprising 473 tumor samples and 195 tumor samples, respectively. Neutrophil contents in these samples were estimated using CIBERSORT, xCell, and microenvironment cell populations (MCP) counter tools. Differentially expressed genes (DEGs) were identified using DEseq2, and a weighted gene co-expression network analysis (WGCNA) was performed to identify neutrophil-related genes. A least absolute shrinkage and selection operator (LASSO) Cox regression model was constructed for prognosis prediction, and the model's accuracy was validated using Kaplan-Meier survival curves and time-dependent receiver operating characteristic (ROC) curves. Additionally, genomic changes, immune correlations, drug sensitivity, and immunotherapy response were analyzed to further validate the model's predictive power. Neutrophil content was significantly higher in adjacent normal tissue compared to LUSC tissue (P<0.001). High neutrophil content was associated with worse overall survival (OS) (P=0.02), disease-free survival (DFS) (P=0.02), and progression-free survival (PFS) (P=0.03) using different software estimates. Nine gene modules were identified, with blue and yellow modules showing strong correlations with neutrophil prognosis (P<0.001). Eight genes were selected for the prognostic model, which accurately predicted 1-, 3-, and 5-year survival in both the training set [area under the curve (AUC) value =0.60, 0.63, 0.66, respectively] and validation set (AUC value =0.58, 0.58, 0.59, respectively), with significant prognosis differences between high- and low-risk groups (P<0.001). The model's independent prognostic factors included risk group, pathologic M stage, and tumor stage (P<0.05). A further molecular mechanism analysis revealed differences between risk groups were revealed in immune checkpoint and human leukocyte antigen (HLA) gene expression, hallmark pathways, drug sensitivity, and immunotherapy responses. This study established a risk-score model that effectively predicts the prognosis of LUSC patients and sheds light on the molecular mechanisms involved. The findings enhance the understanding of neutrophil-tumor interactions, offering potential targets for personalized treatments. However, further experimental validation and clinical studies are required to confirm these findings and address study limitations, including reliance on public databases and focus on a specific lung cancer subtype.

CSF Cytokines and Chemokines Involved in Cytotoxic Cell Function and Risk of Acute 14-Day Mortality in Persons with Advanced HIV and Cryptococcal Meningitis.

Despite availability of HIV treatment globally, cryptococcal meningitis continues to cause considerable morbidity and mortality. The role of the immune response in acute mortality remains unclear. To investigate the immune environment in the central nervous system, cerebrospinal fluid (CSF) from 337 Ugandans with advanced HIV and first-episode cryptococcal meningitis was collected at time of hospitalization. Participants were treated with standard of care amphotericin-B and fluconazole. Cytokines and chemokines in the CSF were quantified and compared by 14-day survival, stratification by quartiles, and logistical regression to determine association with acute mortality. 84 (24.9%) of the participants died by day 14 of hospitalization. Persons who survived to day 14 had higher levels of proinflammatory macrophage inflammatory protein (MIP)-3β and interferon (IFN)-β and cytotoxicity-associated Granzyme-B and inflammatory protein (IP)-10 compared to those who died (P<.05 for each). Logistical regression analysis revealed that per two-fold increase in proinflammatory IL-6, IL-1α, MIP-1β, MIP-3β, and IFN-β and cytotoxicity-associated IL-12, TNF-α, Granzyme-B, and IP-10 CSF concentrations, the risk of acute 14-day mortality decreased. Similar biomarkers were implicated when stratified by quartiles and further identified that lower concentrations of anti-inflammatory IL-10 and IL-13 as associated with 14-day mortality (P<.05 for each). Proinflammatory and cytotoxicity-associated cytokine and chemokine responses in the CSF decrease the risk of acute 14-day mortality. These data suggest that a cytotoxic immune environment in the CSF could potentially improve acute survival. Further research on cytotoxic cells is crucial to improve understanding of innate and adaptive immune responses in cryptococcal meningitis.

A Voyage on the Role of Nuclear Factor Kappa B (NF-kB) Signaling Pathway in Duchenne Muscular Dystrophy: An Inherited Muscle Disorder.

A recessive X-linked illness called Duchenne muscular dystrophy (DMD) is characterized by increasing muscle weakening and degradation. It primarily affects boys and is one of the most prevalent and severe forms of muscular dystrophy. Mutations in the DMD gene, which codes for the essential protein dystrophin, which aids in maintaining the stability of muscle cell membranes during contraction, are the cause of the illness. Dystrophin deficiency or malfunction damages muscle cells, resulting in persistent inflammation and progressive loss of muscular mass. The pathophysiology and genetic foundation of DMD are thoroughly examined in this review paper, focusing on the function of the NF-κB signaling system in the disease's progression. An important immune response regulator, NF-κB, is aberrantly activated in DMD, which exacerbates the inflammatory milieu in dystrophic muscles. Muscle injury and fibrosis are exacerbated and muscle regeneration is hampered by the pro-inflammatory cytokines and chemokines that are produced when NF-κB is persistently activated in muscle cells. The paper also examines our existing knowledge of treatment approaches meant to inhibit the progression of disease by modifying NF-κB signaling. These include new molecular techniques, gene treatments, and pharmacological inhibitors that are intended to lessen inflammation and improve muscle healing. Furthermore covered in the analysis is the significance of supportive care for DMD patients, including physical therapy and corticosteroid treatment, in symptom management and quality of life enhancement. The article seeks to provide a thorough understanding of the mechanisms causing DMD, possible therapeutic targets, and developing treatment options by combining recent research findings. This will provide clinicians and researchers involved in DMD care and research with invaluable insights.