Inflammatory Pathways
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2022 ◽  
Dylan Scott Eiger ◽  
Noelia Boldizsar ◽  
Christopher Cole Honeycutt ◽  
Julia Gardner ◽  
Stephen Kirchner ◽  

Some G protein-coupled receptor (GPCR) ligands act as biased agonists which preferentially activate specific signaling transducers over others. Although GPCRs are primarily found at the plasma membrane, GPCRs can traffic to and signal from many subcellular compartments. Here, we determine that differential subcellular signaling contributes to the biased signaling generated by three endogenous ligands of the chemokine GPCR CXCR3. The signaling profile of CXCR3 changed as it trafficked from the plasma membrane to endosomes in a ligand-specific manner. Endosomal signaling was critical for biased activation of G proteins, β-arrestins, and ERK1/2. In CD8+ T cells, the chemokines promoted unique transcriptional responses predicted to regulate inflammatory pathways. In a mouse model of contact hypersensitivity, β-arrestin-biased CXCR3-mediated inflammation was dependent on receptor internalization. Our work demonstrates that differential subcellular signaling is critical to the overall biased response observed at CXCR3, which has important implications for drugs targeting chemokine receptors and other GPCRs.

npj Vaccines ◽  
2022 ◽  
Vol 7 (1) ◽  
Maxwell L. Neal ◽  
Fergal J. Duffy ◽  
Ying Du ◽  
John D. Aitchison ◽  
Kenneth D. Stuart

AbstractIdentifying preimmunization biological characteristics that promote an effective vaccine response offers opportunities for illuminating the critical immunological mechanisms that confer vaccine-induced protection, for developing adjuvant strategies, and for tailoring vaccination regimens to individuals or groups. In the context of malaria vaccine research, studying preimmunization correlates of protection can help address the need for a widely effective malaria vaccine, which remains elusive. In this study, common preimmunization correlates of protection were identified using transcriptomic data from four independent, heterogeneous malaria vaccine trials in adults. Systems-based analyses showed that a moderately elevated inflammatory state prior to immunization was associated with protection against malaria challenge. Functional profiling of protection-associated genes revealed the importance of several inflammatory pathways, including TLR signaling. These findings, which echo previous studies that associated enhanced preimmunization inflammation with protection, illuminate common baseline characteristics that set the stage for an effective vaccine response across diverse malaria vaccine strategies in adults.

Nutrients ◽  
2022 ◽  
Vol 14 (2) ◽  
pp. 321
Alok K. Paul ◽  
Md K. Hossain ◽  
Tooba Mahboob ◽  
Veeranoot Nissapatorn ◽  
Polrat Wilairatana ◽  

Severe acute respiratory syndrome (SARS)-CoV-2 virus causes novel coronavirus disease 2019 (COVID-19) with other comorbidities such as diabetes. Diabetes is the most common cause of diabetic nephropathy, which is attributed to hyperglycemia. COVID-19 produces severe complications in people with diabetes mellitus. This article explains how SARS-CoV-2 causes more significant kidney damage in diabetic patients. Importantly, COVID-19 and diabetes share inflammatory pathways of disease progression. SARS-CoV-2 binding with ACE-2 causes depletion of ACE-2 (angiotensin-converting enzyme 2) from blood vessels, and subsequently, angiotensin-II interacts with angiotensin receptor-1 from vascular membranes that produce NADPH (nicotinamide adenine dinucleotide hydrogen phosphate) oxidase, oxidative stress, and constriction of blood vessels. Since diabetes and COVID-19 can create oxidative stress, we hypothesize that COVID-19 with comorbidities such as diabetes can synergistically increase oxidative stress leading to end-stage renal failure and death. Antioxidants may therefore prevent renal damage-induced death by inhibiting oxidative damage and thus can help protect people from COVID-19 related comorbidities. A few clinical trials indicated how effective the antioxidant therapy is against improving COVID-19 symptoms, based on a limited number of patients who experienced COVID-19. In this review, we tried to understand how effective antioxidants (such as vitamin D and flavonoids) can act as food supplements or therapeutics against COVID-19 with diabetes as comorbidity based on recently available clinical, preclinical, or in silico studies.

2022 ◽  
Yong-Zheng Zhang ◽  
ZHANG Yong-Zheng ◽  
LI Meng-Jia ◽  
WU Yang ◽  

Abstract Background At present, scholars believe that severe COVID-19 is related to a variety of basic diseases, and we also observe this point using multi-omics method. The latest sequencing data of severe COVID-19 patients were combined to analyze the pathological mechanism, and pharmacological experimental research on local drugs was conducted, and a compound ingredient was found to have potential medicinal value. Results Here, we observed, for patients with severe COVID-19 disease, the differential miRNA expression is mainly low but having higher expression of mRNA. These differential mRNA expressions are associated with the activation of inflammatory pathways and ultimately with hypoxia and coagulation. Using database analysis, we found that Yi Xin Tong Mai Granule(YXTMG) might regulate COVID-19 through Toll-like receptor signaling pathway by acting on different immune targets. We found a new molecular mechanism for COVID-19 to turn the crisis around, the down-regulated miR-181a-5p mediates the up-regulation of PLAU and SERPINE1 molecules to cause cardiovascular adverse events, and YXTMG may prevent it. At the same time, molecular docking indicated that the its various components have anti-inflammatory activity. In vitro studies, we confirmed that YXTMG had antioxidant and anti-inflammatory activities. Conclusions The study has supplemented the potential mechanism for the conversion of mild to critical COVID-19 disease and screened the Chinese medicines for improving these factors, providing methodological reference for disease pathology and drug development.

2022 ◽  
Ling Liu ◽  
Matthew T Buckley ◽  
Jaime M Reyes ◽  
Soochi Kim ◽  
Lei Tian ◽  

Exercise has the ability to rejuvenate stem cells and improve tissue homeostasis and regeneration in aging animals. However, the cellular and molecular changes elicited by exercise have not been systematically studied across a broad range of cell types in stem cell compartments. To gain better insight into the mechanisms by which exercise affects niche and stem cell function, we subjected young and old mice to aerobic exercise and generated a single cell transcriptomic atlas of muscle, neural and hematopoietic stem cells with their niche cells and progeny. Complementarily, we also performed whole transcriptome analysis of single myofibers from these animals. We identified common and unique pathways that are compromised across these tissues and cell types in aged animals. We found that exercise has a rejuvenating effect on subsets of stem cells, and a profound impact in the composition and transcriptomic landscape of both circulating and tissue resident immune cells. Exercise ameliorated the upregulation of a number of inflammatory pathways as well as restored aspects of cell-cell communication within these stem cell compartments. Our study provides a comprehensive view of the coordinated responses of multiple aged stem cells and niche cells to exercise at the transcriptomic level.

2022 ◽  
Rabaa Takala ◽  
Dipak Ramji ◽  
Robert Andrews ◽  
You Zhou ◽  
Mustafa Farhat ◽  

Abstract Objectives: Pinolenic acid (PNLA), an omega-6 polyunsaturated fatty acid from pine nuts, has anti-inflammatory and anti-atherogenic effects. We aimed to investigate the actions of PNLA on activated purified monocytes from peripheral blood of patients with rheumatoid arthritis (RA).Methods: Flow cytometry was used to assess the intracellular expression of TNF-α, IL-6, IL-1β, and IL-8 in purified monocytes from patients with RA after lipopolysaccharide (LPS) stimulation with/without PNLA pre-treatment. The whole genomic transcriptomic (WGT) profile of PNLA-treated, and LPS-activated monocytes from patients with active RA was investigated by RNA-sequencing.Results: PNLA reduced percentage of monocytes expressing the cytokines TNF-α by 23% (p=0.048), IL-6 by 25% (p=0.011), IL-1β by 23% (p=0.050) and IL-8 by 19% (p=0.066). Canonical pathway analysis showed that PNLA inhibited oxidative phosphorylation (p= 9.14E-09) and mitochondrial dysfunction (p=4.18E-08), while the sirtuin (SIRTs) signalling pathway was activated (p=8.89E-06). Pathway analysis predicted upstream activation of peroxisome proliferator-activated receptors (PPARs), sirtuin3, and let7miRNA, which are anti-inflammatory and antioxidative. In contrast, DAP3, LIF and STAT3, which are involved in TNF-α, and IL-6 signal transduction, were inhibited. Many miRNAs were modulated by PNLA suggesting potential post-transcriptional regulation of metabolic and immune response that has not been described previously. Multiple miRNAs target pyruvate dehydrogenase kinase-4 (PDK4), single-immunoglobulin interleukin-1 receptor-related molecule (SIGIRR), mitochondrially encoded ATP synthase membrane subunit 6 (MT-ATP6) and acetyl-CoA acyltransferase 2 (ACAA2); genes implicated in cell metabolism, inflammation, and mitochondrial dysfunction.Conclusion: PNLA has anti-inflammatory and immune-metabolic effects on monocytes that are pathogenic in RA and atherosclerosis. Dietary PNLA supplementation may regulate key miRNAs that are involved in mitochondrial, metabolic, and inflammatory pathways.

Cells ◽  
2022 ◽  
Vol 11 (2) ◽  
pp. 228
Izabella Lice ◽  
José Marcos Sanches ◽  
Rebeca D. Correia-Silva ◽  
Mab P. Corrêa ◽  
Marcelo Y. Icimoto ◽  

Formyl peptide receptors (Fprs) are a G-protein-coupled receptor family mainly expressed on leukocytes. The activation of Fpr1 and Fpr2 triggers a cascade of signaling events, leading to leukocyte migration, cytokine release, and increased phagocytosis. In this study, we evaluate the effects of the Fpr1 and Fpr2 agonists Ac9-12 and WKYMV, respectively, in carrageenan-induced acute peritonitis and LPS-stimulated macrophages. Peritonitis was induced in male C57BL/6 mice through the intraperitoneal injection of 1 mL of 3% carrageenan solution or saline (control). Pre-treatments with Ac9-12 and WKYMV reduced leukocyte influx to the peritoneal cavity, particularly neutrophils and monocytes, and the release of IL-1β. The addition of the Fpr2 antagonist WRW4 reversed only the anti-inflammatory actions of WKYMV. In vitro, the administration of Boc2 and WRW4 reversed the effects of Ac9-12 and WKYMV, respectively, in the production of IL-6 by LPS-stimulated macrophages. These biological effects of peptides were differently regulated by ERK and p38 signaling pathways. Lipidomic analysis evidenced that Ac9-12 and WKYMV altered the intracellular lipid profile of LPS-stimulated macrophages, revealing an increased concentration of several glycerophospholipids, suggesting regulation of inflammatory pathways triggered by LPS. Overall, our data indicate the therapeutic potential of Ac9-12 and WKYMV via Fpr1 or Fpr2-activation in the inflammatory response and macrophage activation.

Stroke ◽  
2022 ◽  
Katherine T. Mun ◽  
Jason D. Hinman

Inflammation and its myriad pathways are now recognized to play both causal and consequential roles in vascular brain health. From acting as a trigger for vascular brain injury, as evidenced by the coronavirus disease 2019 (COVID-19) pandemic, to steadily increasing the risk for chronic cerebrovascular disease, distinct inflammatory cascades play differential roles in varying states of cerebrovascular injury. New evidence is regularly emerging that characterizes the role of specific inflammatory pathways in these varying states including those at risk for stroke and chronic cerebrovascular injury as well as during the acute, subacute, and repair phases of stroke. Here, we aim to highlight recent basic science and clinical evidence for many distinct inflammatory cascades active in these varying states of cerebrovascular injury. The role of cerebrovascular infections, spotlighted by the severe acute respiratory syndrome coronavirus 2 pandemic, and its association with increased stroke risk is also reviewed. Rather than converging on a shared mechanism, these emerging studies implicate varied and distinct inflammatory processes in vascular brain injury and repair. Recognition of the phasic nature of inflammatory cascades on varying states of cerebrovascular disease is likely essential to the development and implementation of an anti-inflammatory strategy in the prevention, treatment, and repair of vascular brain injury. Although advances in revascularization have taught us that time is brain, targeting inflammation for the treatment of cerebrovascular disease will undoubtedly show us that timing is brain.

2022 ◽  
Mona Dastgheib ◽  
Seyed Vahid Shetab-Boushehri ◽  
Maryam Baeeri ◽  
Mahdi Gholami ◽  
Mohammad Yahya Karimi ◽  

Abstract Diabetic neuropathy (DN) is the most challenging microvascular complication of diabetes and there is no suitable treatment for it, so the development of new agents to relieve DN is urgently needed. Since oxidative stress and inflammation play an essential role in the development of DN, clearance of these factors are good strategies for the treatment of this disease. According to key role of cyclic adenosine monophosphate (cAMP) in the regulation of oxidative stress and inflammatory pathways, it seems that phosphodiesterase inhibitors (PDEIs) can be as novel drug targets for improving DN through enhancement of cAMP level. The aim of this study was to evaluate the effects of rolipram, a selective PDE4 inhibitor, and pentoxifylline, a general PDE inhibitor on experimental model of DN and also to determine the possible mechanisms involved in the effectiveness of these agents. We investigated the effects of rolipram (1mg/kg) and pentoxifylline (100 mg/kg) and also combination of rolipram (0.5 mg/kg) and pentoxifylline (50 mg/kg), orally for five weeks in rats that became diabetic by STZ (55 mg/kg, i.p.). After treatments, motor function was evaluated by open-field test, then rats were anesthetized and dorsal root ganglion (DRG) neurons isolated. Next, oxidative stress biomarkers and inflammatory factors were assessed by biochemical and ELISA methods, and RT-PCR analysis in DRG neurons. Rolipram and/or pentoxifylline treatment significantly attenuated DN – induced motor function deficiency by modulating distance moved and velocity. Rolipram and/or pentoxifylline treatment dramatically increased the cAMP level, as well as suppressed DN – induced oxidative stress which was associated with decrease in LPO and ROS and increase in TAC, total thiol, CAT and SOD in DRG neurons. On the other hand, the level of inflammatory factors (TNF-α, NF-kB and COX2) significantly decreased following rolipram and/or pentoxifylline administration.The maximum effectiveness was with rolipram and/or pentoxifylline combination on mentioned factors.These findings provide novel experimental evidence for further clinical investigations on rolipram and pentoxifylline combination for the treatment of DN.

Habib Zouali ◽  
Juliette Lemasson ◽  
Andreea Calugareanu ◽  
Christophe Battail ◽  
David Michonneau ◽  

Cutaneous involvement of chronic graft-versus-host disease (cGVHD) has a wide range of manifestations including a lichenoid form with a currently assumed mixed Th1/Th17 signature and a sclerotic form with Th1 signature. Despite substantial heterogeneity of innate and adaptive immune cells recruited to the skin and of the different clinical manifestations, treatment depends mainly on the severity of the skin involvement, and relies on systemic, high-dose glucocorticoids alone or in combination with a calcineurin inhibitor. We performed the first study using RNAseq to profile and compare the transcriptome of lichen planus cGVHD (n=8), morphea cGVHD (n=5), and healthy controls (n=6). Our findings revealed shared and unique inflammatory pathways to each cGVHD subtype that are both pathogenic and targetable. In particular, the deregulation of IFN signaling pathway was strongly associated with cutaneous cGVHD, whereas the triggering receptor expressed on myeloid cells-1 (TREM-1) pathway was found to be specific of lichen planus and likely contributes to its pathogenesis. The results were confirmed at a protein level by performing immunohistochemistry staining and at a transcriptomic level using Real-Time quantitative PCR.

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