Release Of Inflammatory Mediators Research Articles

Osteoporosis, bisphosphonates, and ocular inflammation.

Osteoporosis, as a musculoskeletal disease, is very common, especially in the era of aging society. It is described by a reduction in bone strength and increased risk of fractures, which are linked to considerable morbidity, mortality, and high healthcare burdens. Bisphosphonates are the most commonly used drugs to manage osteoporosis and they consequently reduce fracture risk. However, one of the clinical challenges is fear of side effects in patients who are using bisphosphonates as the administration of these drugs is lengthy. Ocular inflammation has been reporting as one of the potential vision-threatening side effects of bisphosphonates. To review previously reported ocular inflammation in patients taking bisphosphonates. A literature survey was conducted using databases in order to collect data for a narrative review of published reports regarding ocular side effects of bisphosphonates. People taking bisphosphonates were at a relatively low risk of ocular inflammation, with the onset from a few hours after exposure up to more than 3 years. The release of inflammatory mediators mainly by activated gamma delta T cells in response to bisphosphonates was the main cause of ocular inflammation. Strategies for treating patients with osteoporosis should consider the potential ocular side effects of bisphosphonates. Ocular inflammation, as one of the side effects of bisphosphonates, is a serious sight-threatening sign and should be taken seriously. Greater awareness of the association between bisphosphonate use and ocular inflammation may allow for earlier identification and timely treatment of future cases.

Synthetic Secoisolariciresinol Diglucoside (LGM2605) Prevents Asbestos-Induced Inflammation and Genotoxic Cell Damage in Human Mesothelial Cells.

Although alveolar macrophages play a critical role in malignant transformation of mesothelial cells following asbestos exposure, inflammatory and oxidative processes continue to occur in the mesothelial cells lining the pleura that may contribute to the carcinogenic process. Malignant transformation of mesothelial cells following asbestos exposure occurs over several decades; however, amelioration of DNA damage, inflammation, and cell injury may impede the carcinogenic process. We have shown in an in vitro model of asbestos-induced macrophage activation that synthetic secoisolariciresinol diglucoside (LGM2605), given preventively, reduced inflammatory cascades and oxidative/nitrosative cell damage. Therefore, it was hypothesized that LGM2605 could also be effective in reducing asbestos-induced activation and the damage of pleural mesothelial cells. LGM2605 treatment (50 µM) of huma n pleural mesothelial cells was initiated 4 h prior to exposure to asbestos (crocidolite, 20 µg/cm2). Supernatant and cells were evaluated at 0, 2, 4, and 8 h post asbestos exposure for reactive oxygen species (ROS) generation, DNA damage (oxidized guanine), inflammasome activation (caspase-1 activity) and associated pro-inflammatory cytokine release (IL-1β, IL-18, IL-6, TNFα, and HMGB1), and markers of oxidative stress (malondialdehyde (MDA) and 8-iso-prostaglandin F2a (8-iso-PGF2α). Asbestos induced a time-dependent ROS increase that was significantly (p < 0.0001) reduced (29.4%) by LGM2605 treatment. LGM2605 pretreatment also reduced levels of asbestos-induced DNA damage by 73.6% ± 1.0%. Although levels of inflammasome-activated cytokines, IL-1β and IL-18, reached 29.2 pg/mL ± 0.7 pg/mL and 43.9 pg/mL ± 0.8 pg/mL, respectively, LGM2605 treatment significantly (p < 0.0001) reduced cytokine levels comparable to baseline (non-asbestos exposed) values (3.8 pg/mL ± 0.2 pg/mL and 5.4 pg/mL ± 0.2 pg/mL, respectively). Furthermore, levels of IL-6 and TNFα in asbestos-exposed mesothelial cells were high (289.1 pg/mL ± 2.9 pg/mL and 511.3 pg/mL ± 10.2 pg/mL, respectively), while remaining undetectable with LGM2605 pretreatment. HMGB1 (a key inflammatory mediator and initiator of malignant transformation) release was reduced 75.3% ± 0.4% by LGM2605. Levels of MDA and 8-iso-PGF2α, markers of oxidative cell injury, were significantly (p < 0.001) reduced by 80.5% ± 0.1% and 76.6% ± 0.3%, respectively. LGM2605, given preventively, reduced ROS generation, DNA damage, and inflammasome-activated cytokine release and key inflammatory mediators implicated in asbestos-induced malignant transformation of normal mesothelial cells.

Modulation of Neuroinflammation via Selective Nanoparticle‐Mediated Drug Delivery to Activated Microglia/Macrophages in Spinal Cord Injury

AbstractInflammation after spinal cord injury (SCI) is characterized by immune cell invasion and activation, combined with inflammatory mediator release that worsens outcomes following primary trauma. Effective therapies targeting neuroinflammation remain an unmet need, and modulation of the injury microenvironment to induce a comprehensive pro‐regenerative response is an attractive therapeutic approach. Given its crucial role in cell stress and inflammation after SCI, the potential of pharmacologically targeting MAPK‐activated protein kinase‐2 (MK2) to modulate the response of microglia/macrophages after injury is focused. Nanoparticles (NPs) containing an MK2 inhibitor for specific targeting of microglia/macrophages is developed. NPs selectively target and modulate activated microglia/macrophages in vitro and in a rat model of SCI. NPs in the acute injury setting reduce the pro‐inflammatory cytokine IL‐6 and increase the anti‐inflammatory cytokine IL‐10. Importantly, NPs have a significant effect on microglia/macrophage distribution and accumulation, leading to ≈65% reduction of immune cells around the injury. Last, microglia/macrophage populations with activated morphology are significantly reduced compared to resting or ramified cells around the lesion site. This strategy exhibits potential therapeutic efficiency and specificity for local, pharmacologic manipulation of activated microglia/macrophages, and is a versatile tool to manage acute inflammation and glia plasticity after central nervous system trauma.

Effects of membrane-type PBLs on the expression of TNF-α and IL-2 in pulmonary tissue of SD rats after LPS-induced acute lung injury.

As the first target organ, the lungs usually display symptoms of acute lung injury (ALI). Pro-inflammatory cytokines, such as tumor necrosis factor alpha (TNF-α) and interleukin (IL)-2, are crucial in triggering the systemic inflammatory response syndrome and the subsequent cascading effects. Therefore, the inhibition of the release of inflammatory mediators has become an important strategy for the prevention and treatment of ALI. To evaluate the preventive and therapeutic effects of transmembrane peripheral blood leukocytes (PBLs) on lipopolysaccharide (LPS)-induced ALI and its mechanism. Sixty Sprague Dawley rats were randomly divided into experimental and control groups. The animal model was established through intravenous injection of LPS. Plasmid PBLs were dissolved in a saline solution and injected into the experimental group of rats in different doses (0.1 mg, 0.2 mg and 0.3 mg per rat) using the in situ injection method. After injecting the PBL solution, the rats were killed after 12 h, 24 h, 36 h, or 48 h. The expression of microRNA (miRNA)-25 and miRNA-223 was detected using the semi-quantitative reverse transcription-polymerase chain reaction (RT-PCR). Tumor necrosis factor alpha and IL-2 levels in bronchoalveolar lavage fluid (BALF) were detected with an enzyme-linked immunosorbent assay (ELISA). The expressions of TNF-α and IL-2 proteins in lung tissue were detected using western blotting. The expression of miRNA-25 was upregulated in tissues and BALF in a doseand time-dependent manner, while miRNA-223 was downregulated. The differences were statistically significant compared to the control group (p < 0.05). The TNF-α and IL-2 levels in the BALF of rats in the experimental group were increased in a dose-dependent manner compared to the control group (p < 0.05). In the presence of PBLs, the expressions of TNF-α, IL-2, miRNA, and proteins were inhibited. Thus, PBLs were found to alleviate pulmonary tissue damage. In summary, PBLs have a protective effect on rats with ALI through the downregulation of TNF-α and IL-2 expression.

33431 Efficacy of 80 mg/week dose of adalimumab (Humira) in treatment of hidradenitis suppurativa

Hidradenitis suppurativa (HS) is an inflammatory skin condition involving the apocrine gland-bearing regions, such as the axillae, groin, anogenital, and inframammary areas. Though its etiology is unknown, disease manifests when hair follicles become obstructed, leading to the release of inflammatory mediators, such as TNF-α and IL-17. Levels of TNF-α have been found to be elevated in lesions of HS, providing a basis for the use of biologics in treatment of severe HS. Adalimumab is a recombinant human IgG1 anti-TNF monoclonal antibody which acts via antagonism of TNF-α.

344.4: Kidney Release of Inflammatory Mediators Is Modulated by 17BETA-Estradiol Associated With Methylprednisolone After Brain Death in Female Rats

344.4: Kidney Release of Inflammatory Mediators Is Modulated by 17BETA-Estradiol Associated With Methylprednisolone After Brain Death in Female Rats

33431 Efficacy of 80 mg/week dose of adalimumab (Humira) in treatment of hidradenitis suppurativa

Hidradenitis suppurativa (HS) is an inflammatory skin condition involving the apocrine gland-bearing regions, such as the axillae, groin, anogenital, and inframammary areas. Though its etiology is unknown, disease manifests when hair follicles become obstructed, leading to the release of inflammatory mediators, such as TNF-α and IL-17. Levels of TNF-α have been found to be elevated in lesions of HS, providing a basis for the use of biologics in treatment of severe HS. Adalimumab is a recombinant human IgG1 anti-TNF monoclonal antibody which acts via antagonism of TNF-α. Although adalimumab has been studied in phase 2 and 3 trials and has been approved as a treatment modality for HS at a 40 mg weekly dose, numerous patients still suffer on a day-to-day basis due to the severity of their disease and do not respond to this conventional dosing. We present a series of 6 such patients whose response to an 80 mg/week dose of adalimumab has been positive, with a decrease in severity and number of HS lesions, leading to improvement in the Hidradenitis Suppurativa Clinical Response (HiSCR) in the absence of serious adverse effects. Although this dosing regimen has not been well-documented in literature, it is important to consider the lasting benefits of treatment with a higher dose in individuals afflicted with treatment-resistant HS, including a decreased likelihood of comorbidities and complications and an improved quality of life.

Phase 2 randomized clinical trial of astegolimab in patients with moderate to severe atopic dermatitis

The binding of IL-33 to its receptor ST2 (alias ofIL1RL1) leads to the release of inflammatory mediators and may play a role in the pathogenesis of atopic dermatitis. Astegolimab is a fully human, IgG2 mAb that binds to ST2 and inhibits IL-33 signaling. This study sought to assess the efficacy, safety, and pharmacokinetics of astegolimab in patients with atopic dermatitis. This was a randomized, placebo-controlled, phase 2 study in which adults with chronic atopic dermatitis were randomized 1:1 to receive astegolimab 490 mg every 4 weeks or placebo, for 16 weeks. The primary outcome was the percentage of change from baseline to week 16 of the Eczema Area and Severity Index score. A total of 65 patients were enrolled in the study (placebo, n= 32; astegolimab, n= 33). The adjusted mean percentage of change from baseline to week 16 in the Eczema Area and Severity Index score was -51.47% for astegolimab compared with -58.24% for placebo, with a nonsignificant treatment difference of 6.77% (95% CI: -16.57-30.11; P= .5624). No differences were observed between treatment groups for secondary efficacy outcomes and in exploratory biomarkers (blood eosinophils, serum IL-5, serum CCL13). With the use of loading dose, pharmacokinetic exposure was sufficient from week 1. Astegolimab was well-tolerated, with a safety profile consistent with that observed in previous clinical trials. In patients with atopic dermatitis, astegolimab did not show a significant difference compared to placebo for the primary or secondary outcomes.

6-Shogaol (enexasogoal) treatment improves experimental knee osteoarthritis exerting a pleiotropic effect over immune innate signalling responses in chondrocytes.

The pathogenesis of osteoarthritis implicates a low-grade inflammation associated to the innate immune system activation. Toll like receptor (TLR) stimulation triggers the release of inflammatory mediators, which aggravate osteoarthritis. We studied the preventive effect of 6-shogaol, a potential TLR4 inhibitor, on the treatment of experimental knee osteoarthritis. Osteoarthritis was induced in C57BL6 mice by surgical section of the medial meniscotibial ligament, which received 6-shogaol for eight weeks. Cartilage damage, inflammatory mediator presence and disease markers were assessed in joint tissues by immunohistochemistry. Computational modelling was used to predict binding modes of 6-shogaol into the TLR4/MD2 receptor and its permeability across cellular membranes. Employing LPS-stimulated chondrocytes and MAPK assay, we elucidated 6-shogaol action mechanisms. 6-Shogaol treatment prevented articular cartilage lesions, synovitis and the presence of pro-inflammatory mediators, and disease markers in osteoarthritis animals. Molecular modelling studies predicted 6-shogaol interaction with the TLR4/MD-2 heterodimer in an antagonist conformation through its binding into the MD-2 pocket. In cell culture, we confirmed that 6-shogaol reduced LPS-induced TLR4 inflammatory signalling pathways. Besides, MAPK assay demonstrated that 6-shogaol directly inhibits the ERK1/2 phosphorylation activity. 6-Shogaol evoked a preventive action on cartilage and synovial inflammation in osteoarthritis mice. 6-shogaol effect may take place not only by hindering the interaction between TLR4 ligands and the TLR4/MD-2 complex in chondrocytes, but also through inhibition of ERK phosphorylation, implying a pleiotropic effect on different mediators activated during osteoarthritis, which proposes it as an attractive drug for osteoarthritis treatments.

Bothrops moojeni snake venom induces an inflammatory response in preadipocytes: Insights into a new aspect of envenomation.

Bothrops envenomation is a public health problem in Brazil. Despite the advances in the knowledge of the pathogenesis of systemic and local effects induced by Bothrops venom, the target tissues to this venom are not completely characterised. As preadipocytes are important cells of the adipose tissue and synthesize inflammatory mediators, we investigated the ability of B. moojeni snake venom (Bmv) to stimulate an inflammatory response in 3T3-L1 preadipocytes in vitro, focusing on (1) the release of PGE2, IL-6, TNF-α, MCP-1, KC, leptin and adiponectin; (2) the mechanisms involved in PGE2 release and (3) differentiation of these cells. Cytotoxicity of Bmv was determined by MTT assay. The concentrations of PGE2, cytokines and adipokines were quantified by EIA. Participation of the COX-1 and COX-2 enzymes, NF-κB and PGE2 receptors (EP1-4) was assessed using a pharmacological approach, and protein expression of the COX enzymes and P-NF-κB was analysed by western blotting. Preadipocyte differentiation was quantified by Oil Red O staining. Bmv (1 μg/mL) induced release of PGE2, IL-6 and KC and increased expression of COX-2 in preadipocytes. Basal levels of TNF-α, MCP-1, leptin and adiponectin were not modified. Treatment of cells with SC560 (COX-1 inhibitor) and NS398 (COX-2 inhibitor) inhibited Bmv-induced PGE2 release. Bmv induced phosphorylation of NF-κB, and treatment of the cells with TPCK and SN50, which inhibit distinct NF-κB domains, significantly reduced Bmv-induced PGE2 release, as did the treatment with an antagonist of PGE2 receptor EP1, unlike treatment with antagonists of EP2, EP3 or EP4. Bmv also induced lipid accumulation in differentiating cells. These results demonstrate that Bmv can activate an inflammatory response in preadipocytes by inducing the release of inflammatory mediators; that PGE2 production is mediated by the COX-1, COX-2 and NF-κB pathways; and that engagement of EP1 potentiates PGE2 synthesis via a positive feedback mechanism. Our findings highlight the role of the adipose tissue as another target for Bmv and suggest that it contributes to Bothrops envenomation by producing inflammatory mediators.

Turn Up the HETE on Septic Shock.

Septic shock is life-threatening organ dysfunction due to a dysregulated response to infection. It is a leading cause of death caused by the excessive release of cytokines and inflammatory mediators in response to bacterial endotoxins. It produces hypotension refractory to vasoconstrictors leading to tissue hypoperfusion and multiple organ failure. Despite intensive investigation, there still are no specific pharmacologic treatments. Current therapy relies on supportive care, including antibiotics, fluid resuscitation, corticosteroids, and pressor agents. This commentary summarizes little-known previous observations that inhibition of vascular 20-hydroxyeicosatetraenoic acid (20-HETE) by nitric oxide plays a key role in sepsis. It also highlights the new and exciting current report by Tunctan et al (2022) in this issue of Journal of Cardiovascular Pharmacology that administration of a 20-HETE mimetic can prevent lipopolysaccharide-induced vascular hyporeactivity, hypotension, and tachycardia in rats by activating the recently discovered GPR75/20-HETE receptor. Overall, these results provide a compelling case for initiating 20-HETE clinical trials to prevent hypotension, multiple organ failure, and death in septic shock.

The effect of substance P and its common in vivo-formed metabolites on MRGPRX2 and human mast cell activation.

The tachykinin neuropeptide substance P (SP) is the canonical agonist peptide for the neurokinin 1 receptor (NK1R). More recently, it has also been shown to activate the Mas‐related G protein‐coupled receptor X2 (MRGPRX2) receptor on mast cells (MCs), triggering degranulation and release of inflammatory mediators. SP undergoes rapid C‐terminal truncation in vivo by a number of proteases to generate the metabolites SP(1–9)‐COOH and in particular SP(1–7)‐COOH. While the C terminus of SP is critical for NK1R activation, studies have shown that the peptide polycationic N terminus is key for MRGPRX2 and mast cell activation. The study thus aimed to determine if the C‐terminally truncated metabolites of SP, SP(1–9)‐COOH, and SP(1–7)‐COOH retained stimulatory activity at MRGPRX2. SP, SP(1–9)‐COOH, and SP(1–7)‐COOH were synthesized and tested on HEK293 cells expressing NK1R or MRGPRX2, and LAD2 human mast cells, to determine the activity of SP and its metabolites in Ca2+ mobilization, degranulation, and cytokine assays. As expected from prior studies, both C‐terminally truncated SP metabolites had essentially no activity at NK1R, even at very high concentrations. In contrast, the in vivo metabolite of SP, SP(1–9)‐COOH retained ability to activate MRGPRX2 across all parameters tested, albeit with reduced potency compared to intact SP. SP(1–7)‐COOH did not produce any significant MRGRPX2 activation. Our results suggest that the SP metabolite, SP(1–9)‐COOH, may play a regulatory role through the activation of MRGPRX2. However, given the relatively low potency of both SP and SP(1–9)‐COOH at MRGPRX2, additional work is needed to better understand the biological importance of this expanded SP/MRGPRX2 pathway.

FcγRIIb protects from reperfusion injury by controlling antibody and type I IFN‐mediated tissue injury and death

Intestinal ischemia and reperfusion (I/R) is accompanied by an exacerbated inflammatory response characterized by deposition of IgG, release of inflammatory mediators, and intense neutrophil influx in the small intestine, resulting in severe tissue injury and death. We hypothesized that Fcγ RIIb activation by deposited IgG could inhibit tissue damage during I/R. Our results showed that I/R induction led to the deposition of IgG in intestinal tissue during the reperfusion phase. Death upon I/R occurred earlier and was more frequent in Fcγ RIIb-/- than WT mice. The higher lethality rate was associated with greater tissue injury and bacterial translocation to other organs. Fcγ RIIb-/- mice presented changes in the amount and repertoire of circulating IgG, leading to increased IgG deposition in intestinal tissue upon reperfusion in these mice. Depletion of intestinal microbiota prevented antibody deposition and tissue damage in Fcγ RIIb-/- mice submitted to I/R. We also observed increased production of ROS on neutrophils harvested from the intestines of Fcγ RIIb-/- mice submitted to I/R. In contrast, Fcγ RIII-/- mice presented reduced tissue damage and neutrophil influx after reperfusion injury, a phenotype reversed by Fcγ RIIb blockade. In addition, we observed reduced IFN-β expression in the intestines of Fcγ RIII-/- mice after I/R, a phenotype that was also reverted by blocking Fcγ RIIb. IFNAR-/- mice submitted to I/R presented reduced lethality and TNF release. Altogether our results demonstrate that antibody deposition triggers Fcγ RIIb to control IFN-β and IFNAR activation and subsequent TNF release, tailoring tissue damage, and death induced by reperfusion injury.

Ly6Chi monocytes balance regulatory and cytotoxic CD4 T cell responses to control virus-induced immunopathology.

Gammaherpesviruses (γHVs) have coevolved with their host, leading to a remarkably high infection prevalence and establishment of latency. The lifelong persistence of γHVs in hosts appears to broadly shape host immunity, and we show here that pulmonary infection with Murid herpesvirus 4 (MuHV-4), a mouse γHV, drives the recruitment of Ly6Chi monocytes (MOs) into the airway, thereby modulating the host immune response. The absence of Ly6Chi MOs is associated with severe virus-induced immunopathology and the systemic release of inflammatory mediators. Mechanistically, MuHV-4-imprinted MOs recruit CD4 T cells to the airways and trigger immunosuppressive signaling pathways through the PD-L1/PD-1 axis, thereby dampening the deleterious activation of cytotoxic CD4 T cells. These results uncover a role for Ly6Chi MOs in modulating CD4 T cell functions and reveal pathways that could be targeted therapeutically to reduce detrimental immunopathological responses associated with respiratory viral infections.

Effect of Coffee on Lipopolysaccharide-Induced Immortalized Human Oral Keratinocytes

sPeriodontitis is a common inflammatory disease that is strongly influenced by dietary habits. Coffee is one of the most common dietary components; however, current research on the relationship between coffee consumption and periodontitis, as well as its underlying mechanisms, is limited. Based on a previous report, caffeine (CA) and chlorogenic acid (CGA) were formulated into artificial coffee (AC) for this experiment. Cell viability, prostaglandin E2 release, Western blotting, cellular reactive oxygen species (ROS) production, and NF-E2-related factor 2 (Nrf2) translocation analyses were performed to explore the effects of AC on lipopolysaccharide (LPS)-induced immortalized human oral keratinocytes (IHOKs) and elucidate their underlying mechanisms. AC pretreatment attenuated LPS-induced inflammatory mediator release, ROS production, and nuclear factor kappa B translocation in IHOKs. CA and CGA promoted AMP-activated protein kinase phosphorylation and down-regulated the nuclear factor-κB pathways to exert anti-inflammatory effects. Additionally, CGA promoted Nrf2 translocation and heme oxygenase-1 expression and showed anti-oxidative effects. Furthermore, AC, CA, and CGA components showed synergistic effects. Thus, we predict that coffee consumption may be beneficial for alleviating periodontitis. Moreover, the main coffee components CA and CGA seem to play a synergistic role in periodontitis.

Involvement of a neutrophil-mast cell axis in the effects of Piper malacophyllum (C. PESL) C. DC extract and its isolated compounds in a mouse model of dysmenorrhoea.

The effects of Piper malacophyllum (C. Pesl) C. DC extracts and its isolated compounds were analysed in a mouse model of primary dysmenorrhoea (PD). Female Swiss mice (6-8weeks old) on proestrus were intraperitoneally treated with estradiol benzoate for 3days, to induce PD. Twenty-four hours later, animals were treated 24h later with vehicle, plant extract, gibbilimbol B, 4,6-dimethoxy-5-E-phenylbutenolide, mixture of 4,6-dimethoxy-5-E-phenylbutenolide and 4,6-dimethoxy-5-Z-phenylbutenolide, or ibuprofen. One hour later, oxytocin was injected and the numbers of abdominal writhing were counted. Then, mice were euthanized and uteri were collected for morphometrical and histological analyses. The effects of P. malacophyllum in inflammation were investigated in mouse peritoneal neutrophils culture stimulated with LPS or fMLP (chemotaxis and mediator release). Finally, uterus contractile and relaxing responses were assessed. Similar to ibuprofen, P. malacophyllum extract and isolated compounds reduced abdominal writhing in mice with PD. Histology indicated a marked neutrophil and mast cell infiltrate in the uterus of PD animals which was attenuated by the extract. The compounds and the extract reduced neutrophil chemotaxis and inflammatory mediator release by these cells. Reduced TNF levels were also observed in uteri of PD mice treated with P. malacophyllum. The extract did not affect spontaneous uterine contractions nor those induced by carbachol or KCl. However, it caused relaxation of oxytocin-induced uterine contraction, an effect blunted by H1 receptor antagonist. Overall the results indicate that P. malacophyllum may represent interesting natural tools for reliving PD symptoms, reducing the triad of pain, inflammation and spasmodic uterus behaviour.

Microglia Pyroptosis: A Candidate Target for Neurological Diseases Treatment.

In addition to its profound implications in the fight against cancer, pyroptosis have important role in the regulation of neuronal injury. Microglia are not only central members of the immune regulation of the central nervous system (CNS), but are also involved in the development and homeostatic maintenance of the nervous system. Under various pathological overstimulation, microglia pyroptosis contributes to the massive release of intracellular inflammatory mediators leading to neuroinflammation and ultimately to neuronal damages. In addition, microglia pyroptosis lead to further neurological damage by decreasing the ability to cleanse harmful substances. The pathogenic roles of microglia in a variety of CNS diseases such as neurodegenerative diseases, stroke, multiple sclerosis and depression, and many other neurological disorders have been gradually unveiled. In the context of different neurological disorders, inhibition of microglia pyroptosis by targeting NOD-like receptor family pyrin domain containing (NLRP) 3, caspase-1 and gasdermins (GSDMs) by various chemical agents as well as natural products significantly improve the symptoms or outcome in animal models. This study will provide new ideas for immunomodulatory treatment of CNS diseases.

Immune-Triggered Forms of Plasticity Across Brain Regions.

Immune cells play numerous roles in the host defense against the invasion of microorganisms and pathogens, which induces the release of inflammatory mediators (e.g., cytokines and chemokines). In the CNS, microglia is the major resident immune cell. Recent efforts have revealed the diversity of the cell types and the heterogeneity of their functions. The refinement of the synapse structure was a hallmark feature of the microglia, while they are also involved in the myelination and capillary dynamics. Another promising feature is the modulation of the synaptic transmission as synaptic plasticity and the intrinsic excitability of neurons as non-synaptic plasticity. Those modulations of physiological properties of neurons are considered induced by both transient and chronic exposures to inflammatory mediators, which cause behavioral disorders seen in mental illness. It is plausible for astrocytes and pericytes other than microglia and macrophage to induce the immune-triggered plasticity of neurons. However, current understanding has yet achieved to unveil what inflammatory mediators from what immune cells or glia induce a form of plasticity modulating pre-, post-synaptic functions and intrinsic excitability of neurons. It is still unclear what ion channels and intracellular signaling of what types of neurons in which brain regions of the CNS are involved. In this review, we introduce the ubiquitous modulation of the synaptic efficacy and the intrinsic excitability across the brain by immune cells and related inflammatory cytokines with the mechanism for induction. Specifically, we compare neuro-modulation mechanisms by microglia of the intrinsic excitability of cerebellar Purkinje neurons with cerebral pyramidal neurons, stressing the inverted directionality of the plasticity. We also discuss the suppression and augmentation of the extent of plasticity by inflammatory mediators, as the meta-plasticity by immunity. Lastly, we sum up forms of immune-triggered plasticity in the different brain regions with disease relevance. Together, brain immunity influences our cognition, sense, memory, and behavior via immune-triggered plasticity.

Design and synthesis of novel indole and indazole-piperazine pyrimidine derivatives with anti-inflammatory and neuroprotective activities for ischemic stroke treatment

Microglia-mediated neuroinflammation plays an important role in ischemic stroke (IS). In this work, a series of novel indole and indazole-piperazine pyrimidine derivatives with anti-neuroinflammatory and neuroprotective activities were designed and synthesized for treatment of IS. Among these compounds, 5j displayed the most attractive cytoprotective effect against oxygen-glucose deprivation/reoxygenation (OGD/R)-induced damage in BV2 cells. Meanwhile, it significantly ameliorated the release of inflammatory mediators, including tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), IL-6, nitric oxide (NO) and prostaglandin E2 (PGE2), from lipopolysaccharide (LPS)-induced BV2 cells. Moreover, 5j can decrease the release of TNF-α and IL-1β form LPS-induced mouse brain neuroinflammation model. As a potent inhibitor against both cyclooxygenase-2 (COX-2, IC50 = 92.54 nM) and 5-lipoxygenase (5-LOX, IC50 = 41.86 nM), 5j inhibited the M1 phenotype polarization of microglia and promoted the M2 phenotype polarization of microglia. Additionally, 5j exhibited remarkable neuroprotection in middle cerebral artery occlusion (MCAO) rats by reducing their infarct volumes and neurological deficit scores. In conclusion, 5j has the potential for the treatment of stroke as an anti-inflammatory and neuroprotective agent.

Identification and Validation of a Three Pyroptosis-Related lncRNA Signature for Prognosis Prediction in Lung Adenocarcinoma.

Pyroptosis, defined as programmed cell death, results in the release of inflammatory mediators. Recent studies have revealed that pyroptosis plays essential roles in antitumor immunity and immunotherapy efficacy. Long noncoding RNAs (lncRNAs) are involved in a variety of biological behaviors in tumor cells, although the roles and mechanisms of lncRNAs in pyroptosis are rarely studied. Our study aimed to establish a novel pyroptosis-related lncRNA signature as a forecasting tool for predicting prognosis and ascertaining immune value. Based on lung adenocarcinoma (LUAD) patients from The Cancer Genome Atlas (TCGA), we performed Pearson’s correlation analysis to identify pyroptosis-related lncRNAs. After differentially expressed gene analysis and univariate Cox regression analysis, we selected prognosis-related and differentially expressed lncRNAs. Finally, we performed multivariate Cox regression analysis to establish the three pyroptosis-related lncRNA signature. Kaplan–Meier (KM) survival analyses and receiver operating characteristic (ROC) curves indicated the excellent performance for predicting the prognosis of LUAD patients. At the same time, we applied multidimensional approaches to further explore the functional enrichment, tumor microenvironment (TME) landscape, and immunotherapy efficacy among the different risk groups. A nomogram was constructed by integrating risk scores and clinical characteristics, which was validated using calibrations and ROC curves. Three lncRNAs, namely, AC090559.1, AC034102.8, and AC026355.2, were involved in this signature and used to classify LUAD patients into low- and high-risk groups. Overall survival time (OS) was higher in the low-risk group than in the high-risk group, which was also validated in our LUAD cohort from Shandong Provincial Hospital. TME landscape analyses revealed that a higher abundance of infiltrating immune cells and a greater prevalence of immune-related events existed in the low-risk group. Meanwhile, higher expression of immune checkpoint (ICP) genes, higher immunophenoscore (IPSs), and greater T cell dysfunction in the low-risk group demonstrated a better response to immunotherapy than the high-risk group. Combined with predictions from the Tumor Immune Dysfunction and Exclusion (TIDE) website, we found that LUAD patients in the low-risk group significantly benefited from programmed cell death 1 (PD-1) and cytotoxic T-lymphocyte–associated protein 4 (CTLA4) immune checkpoint blockade (ICB) therapy compared with those in the high-risk group. Furthermore, drug susceptibility analysis identified potential sensitive chemotherapeutic drugs for each risk group. In this study, a novel three pyroptosis-related lncRNA signature was constructed, which could accurately predict the immunotherapy efficacy and prognosis in LUAD patients.