Inflammatory Signaling Research Articles

Gut microbiome-derived lipopolysaccharides aggravate cognitive impairment via TLR4-mediated inflammatory signaling in neonatal rats following hypoxic-ischemic brain damage.

Gut microbiome-derived lipopolysaccharides aggravate cognitive impairment via TLR4-mediated inflammatory signaling in neonatal rats following hypoxic-ischemic brain damage.

STING inhibitors and degraders: Potential therapeutic agents in inflammatory diseases.

STING inhibitors and degraders: Potential therapeutic agents in inflammatory diseases.

Humanised Mice in Cutaneous Leishmaniasis-T-Cell Recruitment Into Human Skin Transplants After Leishmania major Infection.

Treatment against leishmaniasis is associated with severe side effects, high costs, and parasitic resistance. Preclinical models such as humanised mice would aid therapeutic improvement or the development of a vaccine. We developed a model in which human skin transplants on immunodeficient mice are infected with Leishmania major. Parasite inoculation of the skin transplant led to a robust infection with increasing numbers of parasites in the skin and visceral organs. In addition, intraperitoneally co-administered allogeneic peripheral blood mononuclear cells (PBMCs) were strongly recruited to skin lesions, with ≥ 65% of the cells being positive for anti-human CD45; we identified ~20% CD4+ and ~50% CD8+ human T cells. The number of skin-resident macrophages or dendritic cells was unaltered compared to healthy skin prior to transplantation, and PBMC administration did not alter their numbers. Together, we show that parasitic infection provides a strong inflammatory signal that leads to recruitment of T cells into skin transplants. The presence of antigen-presenting cells in the transplants-as an important prerequisite for proper APC-T-cell interaction-recreates a fully human skin microenvironment that allows for stroma/immune cell interactions upon infection. This model may be of high interest to researchers interested in translating skin research questions into the human system invivo.

Investigation of the effect and mechanism of Fei Re Pu Qing powder in treating acute lung injury (ALI) by modulating macrophage polarization via serum pharmacology and network pharmacology.

Investigation of the effect and mechanism of Fei Re Pu Qing powder in treating acute lung injury (ALI) by modulating macrophage polarization via serum pharmacology and network pharmacology.

Homoyessotoxin alleviates inflammatory responses by regulating the TLR4/MyD88/NFκB and Nrf2/HO-1 pathways.

Homoyessotoxin alleviates inflammatory responses by regulating the TLR4/MyD88/NFκB and Nrf2/HO-1 pathways.

D-RADA16 self-assembling peptide microneedle patches alleviate osteoarthritis inflammation by inhibiting mtDNA leakage-mediated cGAS-STING pathway.

D-RADA16 self-assembling peptide microneedle patches alleviate osteoarthritis inflammation by inhibiting mtDNA leakage-mediated cGAS-STING pathway.

Protective role of dietary short chain fatty acid propionate against autoimmune responses and pathology of systemic lupus erythematosus in MRL-lpr mice.

Protective role of dietary short chain fatty acid propionate against autoimmune responses and pathology of systemic lupus erythematosus in MRL-lpr mice.

Distinct transcriptional changes in hematopoietic progenitor subsets on LPS-induced emergency granulopoiesis.

Distinct transcriptional changes in hematopoietic progenitor subsets on LPS-induced emergency granulopoiesis.

The Effects of Tocilizumab on Inflammatory and Differentiation Pathways in Primary Human Chondrocytes: A Bioinformatic and In Vitro Approaches

ABSTRACTIntroductionThis study investigates the effects of Tocilizumab, an interleukin‐6 (IL‐6) receptor inhibitor, on human primary chondrocyte cells, focusing on bone morphogenetic protein 2 (BMP‐2), hypoxia‐inducible factor 1‐alpha (HIF‐1α), interleukin‐1 beta (IL‐1β), SRY‐box transcription factor 9 (SOX‐9), and IL‐6 genes.MethodsCombining bioinformatic and experimental approaches, we assessed Tocilizumab's impact on inflammatory signaling pathways, cellular differentiation, and viability. Reactome and Gene Ontology (GO) enrichment analyses revealed the involvement of interleukin signaling, BMP, and mitogen‐activated protein kinase (MAPK) pathways.ResultsProtein–protein interaction (PPI) network analysis indicated strong interactions among the studied genes, with BMP‐2 and SOX‐9 identified as central nodes. Western blot analysis demonstrated a 71% reduction in SOX‐9, a 55% reduction in HIF‐1α, and an 81% reduction in BMP‐2 expression levels by day 15. Conversely, IL‐1β levels decreased by 67% after prolonged treatment. MTT assays showed a 27.7% reduction in cell viability at day 15 compared to controls. Despite these changes, staining analyses confirmed preserved cell membrane integrity and nuclear morphology, indicating minimal cytotoxic effects.ConclusionThese findings highlight Tocilizumab's role in modulating inflammation and differentiation pathways in human primary chondrocytes. Further studies should explore the long‐term effects of IL‐6 blockade on cartilage remodeling and regenerative capacity in chronic inflammatory settings.

Integrative network pharmacology and experimental validation of anti-inflammatory triterpenoids from hawthorn leaves

A network pharmacology approach was employed to identify key bioactive compounds and core targets in hawthorn leaves with potential anti-inflammatory properties. The predicted biological effects and underlying mechanisms were systematically validated through target enzyme activity evaluations, molecular docking simulations, LPS-induced inflammatory models in RAW264.7 macrophages, western blot and quantitative real-time PCR (qRT-PCR) analyses. Molecular docking studies revealed strong binding affinities of triterpenoids 99, 102, and 116 to SRC (Proto-Oncogene Tyrosine-Protein Kinase Src), a critical regulator of inflammatory signaling pathways. These interactions were further substantiated by enzymatic activity assays and macrophage-based inflammatory models. Notably, the triterpenoids showed strong anti-inflammatory properties by significantly reducing nitric oxide (NO) release and altering the expression of inflammatory genes in LPS-stimulated RAW264.7 macrophages. Among them, triterpenoid 99 demonstrated the most pronounced activity, primarily by downregulating SRC mRNA and protein expression. These findings provide compelling scientific evidence supporting the use of hawthorn leaves as a natural reservoir of anti-inflammatory agents, offering a strong foundation for future pharmacological and therapeutic developments.

Based on the IL-33/ST2-MyD88 signaling pathway to explore the mechanism of aerobic exercise in antagonizing the inflammatory response in depressive mice.

Based on the IL-33/ST2-MyD88 signaling pathway to explore the mechanism of aerobic exercise in antagonizing the inflammatory response in depressive mice.

Evaluating the Effects of Imiquimod on Paths of TLRs and Inflammatory Cytokines Signaling in Infected Macrophages with Leishmania major in Vitro and in Vivo

Background: Leishmania major is an obligate and intracellular pathogen and the macrophages are the cell hosts for L. major. Imiquimod stimulates macrophages to secrete different cytokines via the expression of TLRs. Methods: This study was carried out in the Department of Parasitology, Faculty of Medical Sciences, Tarbiat Modares University, in 2018. The effect of imiquimod was investigated on non-infected and infected macrophages with L. major on the expression of Toll-like receptors (TLRs) and inflammatory cytokines. TLRs play an important role in enhancing the proceeding of phagocytosis and killing parasites. Moreover, the cytokines such as TNFα, IL6, and IL1, are often identified in inflammatory conditions as interfering targets in treatment. Healthy macrophages and macrophages infected with Leishmania major parasites were affected by different concentrations of imiquimod, after that the expression of TLR genes (TLR1, TLR2, TLR3, TLR4, TLR7 and TLR9) and cytokines were evaluated by real time RT-PCR. For experiments in laboratory animals, infected BALB/c mice were exposed to imiquimod and then isolated peritoneal macrophages. Results: The expression of TLR2 decreased in non-infected macrophages were affected by the imiquimod. The expression level of TLR7 in healthy macrophages, decreased and the difference with control group was significant. Imiquimod increases the expression of inflammatory cytokines and IL12 in mouse macrophages and also decrease the expression of IL10. Conclusion: This suggests that imiquimod may improve the therapeutic effects in infected mice with Leishmania major. Imiquimod causes that TLR2 decreased expression but TLR7 and TLR9 increased expression. Imiquimod as TLR7 agonist, enhance the recovery of leishmaniasis.

Administration of Purified Alpha-1 Antitrypsin in Salt-Loaded Hypertensive 129Sv Mice Attenuates the Expression of Inflammatory Associated Proteins in the Kidney

Background: Alpha-1 antitrypsin (AAT) is a multifunctional protease inhibitor that has been shown to have anti-inflammatory properties in various diseases. AAT has been reported to protect against renal injury via anti-apoptotic, anti-fibrotic, and anti-inflammatory effects. However, its role in mitigating renal inflammation and reducing high blood pressure induced by salt-loading has never been studied. Methods: In this study, we salt-loaded 129Sv mice to induce hypertension and then administered purified human AAT (hAAT) or the vehicle to investigate whether renal inflammation and associated inflammatory/signaling pathways are mitigated. Results: Western blotting and densitometric analysis showed administration of hAAT attenuated protein expression of kidney injury molecule-1 (KIM1), CD93, CD36, and the toll-like receptor 2 and 4 (TLR-2/4) in kidney lysates. Similarly, protein expression of two key inflammatory transcription factors, signal transducer and activator of transcription 3 (STAT3) and NF-Kappa B were shown to be attenuated in the kidneys of 129Sv mice that received hAAT. Conversely, hAAT treatment upregulated the expression of heat shock protein 70 (HSP70) and immunohistochemistry confirmed these findings. Conclusions: Purified hAAT administration may be efficacious in mitigating renal inflammation associated with the development of hypertension from salt-loading, potentially through a mechanism involving the reduction of pro-inflammatory and injury-associated proteins.

Genetic ancestry shapes dengue virus infection in human skin explants

Dengue is the most prevalent arthropod-borne viral disease of humans, with over half the world's population at risk. Infection with any of the four dengue virus (DENV) serotypes is most often self-limiting, but a significant number of cases present with severe dengue characterized by vascular leakage that may be fatal. African ancestry is associated with protection against severe dengue, but the mechanisms are unknown. Using skin explants from genetically defined donors, we show that European ancestry skin has a much stronger inflammatory response to DENV than African ancestry skin, eliciting markedly increased infiltration, infection and migration of resident Langerhans cells, macrophages, and dendritic cells. The effect was seen with all dengue serotypes and Zika virus and in the presence of heterotypic immune serum. Genetic pathways associated with inflammation, interferon (IFN)-α, and inflammatory cytokine signaling were enriched in European relative to African ancestry skin following infection. Infiltration and infection of macrophages in African ancestry skin increased to that of European skin after blocking IFN-α and providing interleukin-1β. Polymorphic variants in RXRA, OAS1-3, and TGFB1 genes that were more frequent in European donors were associated with increased virus replication. Paradoxically, European ancestry skin cells had increased expression of OAS3 in response to virus and type I IFN. Thus, the limited inflammatory response of African ancestry skin to infection restricts replication and spread of dengue and other flaviviruses. Genetic ancestry should be considered when predicting a patient's likelihood of severe dengue, and when assessing efficacy and adverse events associated with dengue vaccines.

Akkermansia muciniphila‐Derived Outer Membrane Vesicles as a Novel Therapeutic Approach for Mastitis: Insights From In Vitro and Vivo Studies

ABSTRACTMastitis is a major disease affecting the dairy industry. Although antibiotics are the most prevalent treatment for mastitis, their overuse presents significant risks to public health. Probiotic therapy has emerged as a promising alternative for controlling mastitis, but there is a lack of comprehensive studies on the efficacy and mechanisms of specific probiotics in treating this condition. Here, we investigate the potential of Akkermansia muciniphila (A. muciniphila) and its derived outer membrane vesicles (AOMVs) as therapeutic agents for mastitis. Significant differences in microbial communities were identified through an analysis of the microbiota composition in milk from healthy and mastitis cows. Spearman's correlation analysis revealed a significant negative correlation between the relative abundances of Verrucomicrobia and Akkermansia and the levels of inflammatory cytokines in mastitis milk. Furthermore, we evaluated the roles of live and pasteurized A. muciniphila in lipopolysaccharide (LPS)‐induced inflammatory responses in bovine mammary epithelial cells (MAC‐T). Compared to pasteurized A. muciniphila, live A. muciniphila exhibited a stronger anti‐inflammatory effect, notably inhibiting the TLR4 and NF‐κB signaling pathways. We also demonstrated that these effects of A. muciniphila may be mediated through AOMVs. Subsequently, the therapeutic potential of AOMVs was evaluated in vivo using an LPS‐induced mastitis mouse model. The results demonstrated that AOMVs targeted the mammary glands, alleviated LPS‐induced damage, and reduced inflammatory cytokine levels and signaling pathway activation. Finally, we conducted a preliminary investigation to assess the therapeutic effects of A. muciniphila on mastitis in dairy cows. Administration of A. muciniphila significantly reduced somatic cell count (SCC) in the milk of cows with mastitis. Notably, four of the five treated cows showed a decrease in SCC to below 2 × 105 cells/mL, with negative results in the California Mastitis Test. Our findings provide compelling evidence for the therapeutic potential of A. muciniphila and AOMVs in the treatment of mastitis. These results not only highlight the anti‐inflammatory properties of A. muciniphila as a potential probiotic, proposing novel strategies for developing alternatives to antibiotic therapies, but also provide a theoretical basis for exploring the role of outer membrane vesicles in the host‐microbe interface.

Epigenetic erosion of H4K20me1 induced by inflammation drives aged stem cell ferroptosis.

Aging is characterized by a decline in the functionality and number of stem cells across the organism. In this study, we uncovered a mechanism by which systemic inflammation drives muscle stem cell (MuSC) aging through epigenetic erosion. We demonstrate that age-related inflammation decreases monomethylation of H4K20 in MuSCs, disrupting their quiescence and inducing ferroptosis, a form of iron-dependent cell death. Our findings show that inflammatory signals downregulate Kmt5a, the enzyme responsible for depositing H4K20me1, leading to the epigenetic silencing of anti-ferroptosis genes. This results in aberrant iron metabolism, increased reactive oxygen species levels and lipid peroxidation in aged MuSCs. Notably, long-term inhibition of systemic inflammation that is initiated at 12 months of age effectively prevents ferroptosis, preserves MuSC numbers and enhances muscle regeneration and functional recovery. These findings reveal an epigenetic switch that links chronic inflammation to MuSC aging and ferroptosis, offering potential therapeutic strategies for combating age-related muscle degeneration.

Neuro-inflammation Induced by Arsenic: An Insight into Mechanisms and Pathways Involved.

Neuroinflammation is increasingly recognized as a critical factor in the progression of various neurological disorders, with chronic exposure to environmental toxicants like arsenic emerging as a major contributor. This review focuses on arsenic-induced neuroinflammation, highlighting its underlying molecular mechanisms and pathways, global epidemiological burden, and current strategies for effective management. Arsenic groundwater contamination, particularly prevalent in Asian countries, poses a significant health risk to millions across more than 100 nations. Chronic exposure to arsenic generates reactive oxygen species (ROS), triggering oxidative stress and activating microglia, the key drivers of neuroinflammation. This cascade promotes proinflammatory cytokine release, leading to cognitive and neurological impairments. This review examines the underlying mechanisms, including mitochondrial dysfunction, oxidative damage, and inflammatory signaling pathways. Additionally, this review highlights current therapeutic strategies aimed at mitigating arsenic-induced neurotoxicity, including chelation therapy, natural antioxidants, and supplementation with essential trace elements. By addressing the multifactorial mechanisms underlying arsenic-induced neuroinflammation, the review emphasizes the urgent need for integrated public health initiatives and targeted interventions to alleviate the neurological consequences of chronic arsenic exposure.

Protective effects of taxifolin against gentamicin-induced nephrotoxicity in mice: modulation of oxidative stress, inflammation, apoptosis, and Nrf2 signaling.

Gentamicin (GEN), an antibiotic belonging to aminoglycosides, is commonly administered to treat gram-negative bacterial infections. However, GEN nephrotoxicity restricts its therapeutic applications. The study examined the nephroprotective efficiency of a plant flavonoid (Taxifolin, TX) against GEN-associated renal damage in mice. Oral administration of TX (25 or 50mg/kg/day) in mice for 14days was followed by intraperitoneal GEN (100mg/kg/day) treatments from the 8th to 14th day. GEN-treated mice were characterized by higher creatinine and urea levels in the serum and significant renal histopathological modifications. They also presented elevated malondialdehyde (MDA) and protein carbonyl and decreased levels of reduced glutathione(GSH) and activities of catalase(CAT), and superoxide dismutase(SOD). TX effectively improved renal function and antioxidant potential while simultaneously lowering MDA and protein carbonyl levels in GEN-administered mice. Furthermore, TX suppressed the renal expressions of nuclear factor kappa B (NF-κB) p65 and decreased levels of interleukin-6 (IL-6) and tumor necrosis factor alpha (TNF-α) in GEN-treated mice. GEN treatment increased caspase-3 and Bcl-2 associated X (Bax) and reduced B-cell lymphoma-2 (Bcl-2) protein levels in mouse kidneys. These effects were significantly mitigated by TX treatment. GEN administration significantly suppressed nuclear factor erythroid 2-related factor 2 (Nrf2) and heme oxygenase-1 (HO-1) protein levels in mouse kidneys. Largely, TX restored renal Nrf2 and HO-1 protein levels, as evidenced by immunohistochemistry and ELISA analyses, respectively, in GEN-treated mice. Overall, TX provided nephroprotection against GEN-induced kidney damage via modulation of oxidative stress, inflammation, and apoptosis and restoration of Nrf2 signaling. Thus, TX could be a promising adjuvant candidate to prevent drug-linked organ injury.

Lipopolysaccharide and Recombinant Prion Protein Induce Distinct Neurodegenerative Pathologies in FVB/N Mice

Prion diseases are classically attributed to the accumulation of protease-resistant prion protein (PrPSc); however, recent evidence suggests that alternative misfolded prion conformers and systemic inflammatory factors may also contribute to neurodegeneration. This study investigated whether recombinant moPrPRes, generated by incubating wild-type mouse PrPC with bacterial lipopolysaccharide (LPS), can induce prion-like disease in FVB/N female mice, whether LPS alone causes neurodegeneration, and how LPS modulates disease progression in mice inoculated with the Rocky Mountain Laboratory (RML) strain of prions. Wild-type female FVB/N mice were randomized into six subcutaneous treatment groups: saline, LPS, moPrPRes, moPrPRes + LPS, RML, and RML + LPS. Animals were monitored longitudinally for survival, body weight, and clinical signs. Brain tissues were analyzed histologically and immunohistochemically for vacuolar degeneration, PrPSc accumulation, reactive astrogliosis, and amyloid-β plaque deposition. Recombinant moPrPRes induced a progressive spongiform encephalopathy characterized by widespread vacuolation and astrogliosis, yet with no detectable PrPSc by Western blot or immunohistochemistry. LPS alone triggered a distinct neurodegenerative phenotype, including cerebellar amyloid-β plaque accumulation and terminal-stage spongiosis, with approximately 40% mortality by the end of the study. Co-administration of moPrPRes and LPS resulted in variable regional pathology and intermediate survival (50% at 750 days post-inoculation). Interestingly, RML + LPS co-treatment led to earlier clinical onset and mortality compared to RML alone; however, vacuolation levels were not significantly elevated and, in some brain regions, were reduced. These results demonstrate that chronic endotoxemia and non-infectious misfolded PrP conformers can independently or synergistically induce key neuropathological hallmarks of prion disease, even in the absence of classical PrPSc. Targeting inflammatory signaling and toxic prion intermediates may offer novel therapeutic strategies for prion and prion-like disorders.

Aluminum Disrupts Motor Function, Cholinergic System, Redox Balance, Pro-Apoptotic and Pro-Inflammatory Pathways in Nauphoeta cinerea Model.

This study sought to investigate the utility of the lobster cockroach (Nauphoeta cinerea) to understand the effect of aluminum (Al) exposure on neural tissues. We randomly divided lobster cockroach nymphs into three groups: control, 125mg/g AlCl₁, and 250mg/g AlCl₁. The cockroaches were maintained on an Al-containing dietary regimen for 3, 7 and 14 days and subsequently assessed for neurolocomotor indices. Cockroach heads were then dissected on ice and the neural tissues were isolated to assay cell viability, acetylcholinesterase, monoamine oxidase, glutathione-S-transferase, total thiol and total reactive oxygen and nitrogen species (RONS). In addition, mRNA levels of antioxidant, PI3K/AKT pro-apoptotic and JNK/UPD3 pro-inflammatory pathway genes were analyzed on day 14. Locomotor indices were reduced during these exposure periods, but there was no significant difference in the survival rate of the cockroaches. The biochemical analysis revealed a significant increase in AChE activity in Al-exposed cockroaches across the three points of analysis, while cell viability and mRNA levels of superoxide dismutase, catalase and thioredoxin were significantly reduced by day 14. Furthermore, significant increases in total RONS, total thiol, GST activity, and mRNA levels of GST, DUOX, Akt, Egr, Pvf and upd3 were observed in Al-exposed groups. Al-induced impairments were largely dose- and time-dependent. Collectively, we demonstrated, for the first time, the utility of Nauphoeta cinerea to delineate the mechanisms of Al-induced neurotoxicity and neurodegeneration. The behavioral deficits were accompanied by increased AChE activity and ROS production, impairment of the antioxidant system, and modulation of the PI3K/Akt and JNK/upd3 signaling pathways that modulate apoptosis and inflammatory signals, respectively.