Inflammation Research最新文献

Background: Sepsis and heatstroke, although arising from microbial infection or environmental heat exposure, converge upon similar pathophysiological systemic inflammatory responses that include immune dysregulation, mitochondrial dysfunction, endothelial injury, and multiorgan failure. Despite this overlap, important mechanistic differences, especially in the initiating triggers and immune response dynamics, distinguish their clinical manifestations and therapeutic strategies.

Findings: Sepsis is initiated by pathogen-associated molecular patterns (PAMPs) recognized by pattern recognition receptors, whereas heatstroke stems from the release of damage-associated molecular patterns (DAMPs) in response to thermal injury. Both syndromes disrupt mitochondrial integrity, leading to impaired oxidative phosphorylation, an excess production of reactive oxygen species (ROS), and the release of mitochondrial DNA and cytochrome C, which further amplify inflammation and promote cell death. Leukocytes undergo diverse forms of death-including apoptosis, necroptosis, pyroptosis, and ferroptosis-compounding immune dysfunction. Coagulopathy and disseminated intravascular coagulation are prevalent in both conditions, driven by endothelial injury, platelet activation, and NET formation, although microbial toxins intensify this response in sepsis.

Conclusions: This review synthesizes current evidence to delineate the converging and diverging pathways of sepsis and heatstroke, with a focus on mitochondrial injury, immune paralysis, and thromboinflammation. We also explore emerging biomarkers and novel therapeutic targets, including mitochondrial stabilizers and modulators of cell death. A comprehensive understanding of these mechanisms can inform precision medicine strategies and improve outcomes in both syndromes.

Objective: Mitogen-activated protein kinase phosphatase-1 (MKP-1) is an anti-inflammatory enzyme whose expression is increased by glucocorticoids (GCs). MKP-1 dephosphorylates and thereby inactivates mitogen-activated protein kinases (MAP kinases) which are major signaling pathways mediating proinflammatory effects of various extracellular factors to gene expression. In this study, we examined the regulatory effects of the synthetic glucocorticoid dexamethasone on the expression of a panel of genes previously identified as the top 15 critical mediators in the pathogenesis of osteoarthritis (OA). Furthermore, we investigated the hypothesis that MKP-1 is involved in mediating these glucocorticoid-induced effects in chondrocytes.

Methods: The effects of dexamethasone on the interleukin-1β-induced expression of OA target genes were investigated with RNA-seq and quantitative RT-PCR in primary cultured chondrocytes from wild-type and MKP-1 deficient mice, and from OA patients undergoing joint replacement surgery.

Results: Under these conditions, dexamethasone was found to significantly alter the expression of seven out of the 15 OA-related genes including two cholesterol hydroxylases, namely cholesterol 25-hydroxylase (CH25H) and 25-hydroxycholesterol 7-hydroxylase (also known as cytochrome P450 family 7 subfamily B member 1, CYP7B1). Dexamethasone attenuated the interleukin-1β -induced expression of CH25H and CYP7B1 in primary chondrocytes of wild-type mice and in primary human OA chondrocytes, but the dexamethasone effect was absent (CYP7B1) or reduced (CH25H) in chondrocytes from MKP-1 deficient mice. Furthermore, the p38 MAP kinase inhibitor BIRB796 significantly inhibited CH25H expression while the JNK MAP kinase inhibitor SP600125 attenuated CYP7B1 expression in human OA chondrocytes.

Conclusions: In conjunction with previous findings, the current data substantiate the role of MKP-1 as a protective factor in chondrocytes and highlight its potential as a therapeutic target for the treatment of osteoarthritis, because increased levels of cholesterol and its metabolism by CH25H and CYP7B1 are involved in the pathogenesis of OA, particularly in its obesity-associated phenotype.

The OX40/OX40L co-stimulatory signaling pathway plays a crucial role in T cell activation, differentiation, expansion, and survival across various human tissues, including the skin and mucosal surfaces. Alterations in this pathway have been implicated in diverse immune-mediated skin conditions such as tumor microenvironments; atopic dermatitis, characterized by type 2 inflammation; psoriasis and hidradenitis suppurativa, associated with Th17 responses; vitiligo, involving dysregulated interferon-producing CD8⁺ T cells. The complex interplay between mast cells expressing OX40L and T cells expressing OX40, which in some contexts can inhibit regulatory T cell (Treg) function and promote Th17 differentiation, underscores the therapeutic potential of either antagonizing or agonizing this co-stimulatory pathway. In this review, we discuss selected dermatological diseases in which the OX40/OX40L axis appears relevant to their immunopathogenesis and may serve as a potential therapeutic target.

Objective: Colitis disrupts the intestinal barrier, leading to increased permeability and the translocation of harmful microbial components into the circulation and distant organs, including bone. Given that macrophages serve as both frontline immune defenders in tissues and key regulators of bone homeostasis, this study investigates molecular alterations in osteal macrophages (Omacs) and their contribution to bone loss in a murine model of colitis-induced osteoporosis.

Methods: Colitis-induced osteoporosis was established by administering DSS in drinking water for 5 days. Omacs were isolated from bone tissue and subjected to bulk RNA-seq analysis, phagocytosis assays and co-culture models with osteoblasts or osteoclast precursors.

Results: RNA-seq data of Omcas demonstrated a shift towards an inflammatory phenotype under colitis conditions, which was accompanied by bone loss in mice. The upregulated genes in these cells were most significantly enriched in IL-17, NF-κB, and TNF signaling pathways. Importantly, these cells exhibited decreased phagocytic activity and were able to disrupt osteoblast differentiation and promote osteoclast differentiation in vitro.

Conclusions: These results indicate that colitis triggers a significant inflammatory response in Omacs, which can contribute to bone metabolic dysfunction. Modulating the activation of inflammatory pathways may offer a potential therapeutic avenue for treating colitis-induced osteoporosis.

Objective: T cell immunoglobulin and mucin-domain containing-3 (TIM-3) plays a critical regulatory role in a variety of diseases. Human soluble TIM-3 (sTIM-3) is known to be generated through proteolytic cleavage of membrane-bound TIM-3 by the A disintegrin and metalloprotease, however its precise role in inflammation remains largely unclear. This study aims to define the specific function of sTIM-3.

Methods: In this study, the role of sTIM-3 was investigated using in vivo models of experimental autoimmune encephalomyelitis (EAE) and septic shock. Mechanistic insights were gained through biochemical analyses of the NACHT, LRR and PYD domains-containing protein 3 (NLRP3) inflammasome pathway.

Results: We found that sTIM-3 alleviated disease severity in both EAE and septic shock. This protective effect was achieved through the inhibition of NLRP3 inflammasome activation. Mechanistically, sTIM-3 interacted with the adaptor protein Apoptosis-associated speck-like protein containing a CARD (ASC), thereby dampening its oligomerization and subsequent assembly of the active NLRP3 inflammasome complex.

Conclusion: Our findings establish sTIM-3 as a promising therapeutic candidate for mitigating inflammation caused by excessive NLRP3 inflammasome activation, providing novel insights into potential interventions for various inflammatory diseases.

Background: Periodontitis has been associated with an increased risk of atherosclerotic cardiovascular disease; however, its association with subclinical myocardial injury remains scarce. The purpose of this study was to investigate the association between periodontitis, cardiac biomarkers of subclinical myocardial injury, and cardiovascular mortality in the general U.S.

Population:

Methods: We analyzed data from 9202 participants initially free of cardiovascular disease in the 1999-2004 National Health and Nutrition Examination Survey. The grade of periodontitis was categorized into normal, mild, and moderate-severe. Survey-weighted multiple linear regression model assessed the association between periodontitis and cardiac biomarkers, including high-sensitivity cardiac troponin (hs-cTn) and N-terminal pro-B-type natriuretic peptide (NT-proBNP). Survey-weighted multiple Cox regression model was utilized to estimate the association between periodontitis and cardiovascular disease mortality.

Results: The mean age of participants was 40.65 ± 0.32 years, with 48.44% being men. The individuals with mild and moderate-severe periodontitis had significantly elevated hs-cTn and NT-proBNP, which indicated impaired cardiac structure and function, compared with non-periodontitis individuals. After controlling confounding covariates, moderate-severe periodontitis was significantly correlated with elevated hs-cTnT and NT-proBNP (β coefficients: 0.055, 95% CI 0.004 to 0.106; β coefficients: 0.188, 95% CI 0.077 to 0.300, respectively). Sensitivity analysis and subgroup analysis further verified the robustness of the results. Over a 17.5-year follow-up period, individuals with moderate-to-severe periodontitis exhibited a 44.9% higher risk of cardiovascular mortality compared to those without periodontitis (hazard ratio: 1.449, 95% CI: 1.027 to 2.044).

Conclusion: In individuals without established cardiovascular disease, moderate-severe periodontitis was associated with higher concentrations of hs-cTn and NT-proBNP, as well as an increased risk of cardiovascular mortality. These results emphasize the importance of maintaining optimal oral health.

Background: Psoriatic disease (PsD) is a chronic systemic inflammatory condition associated with significant cardiometabolic comorbidities, including obesity, type 2 diabetes mellitus (T2DM), and cardiovascular (CV) disease. These comorbidities are interlinked via shared immunopathogenic mechanisms, notably chronic low-grade inflammation driven by Th1/Th17 cytokines such as TNF, IL-6, and IL-17. Obesity, in particular, exacerbates PsD severity and treatment resistance, underscoring the need for integrated therapeutic strategies. This scoping review investigates the biological rationale and evidence for the use of glucagon-like peptide-1 receptor agonists (GLP-1RAs) in PsD.

Findings: Originally developed for T2DM, GLP-1RAs have demonstrated efficacy in reducing weight and improving glycemic control and CV outcomes. Evidence also suggests immunomodulatory properties through modulation of key inflammatory pathways and immune cell activity. We examined studies addressing: (1) the impact of obesity, T2DM, and CV disease on PsD; (2) outcomes of GLP-1RAs in these comorbidities; and (3) their potential in related rheumatologic and dermatologic diseases. GLP-1RAs show promise in reducing PsD burden by improving metabolic parameters and reducing systemic inflammation. Early clinical and preclinical data suggest benefits also in rheumatoid arthritis, osteoarthritis, osteoporosis, psoriasis, and hidradenitis suppurativa.

Implications: GLP-1RAs represent a novel, multifaceted therapeutic option in PsD, targeting both metabolic and inflammatory components. Further clinical trials are warranted to define their role in comprehensive PsD management and validate their disease-modifying potential.

Wound healing is a complex and tightly controlled physiological process that involves various cell types, among which macrophages play a critical role in tissue repair and regeneration. Transcription regulators influence gene expression in macrophages at several phases of wound healing, such as hemostasis, inflammation, proliferation, and remodeling. This article explores the transcription factors that regulate the activity of macrophages during wound healing and help in ECM remodeling. Understanding how these transcription regulators coordinate macrophage actions in response to cellular and molecular stimuli is essential for determining the process behind acute and chronic healing. This review highlights the therapeutic interventions through modulating transcriptional activity to improve wound healing and resolve fibrosis in chronic wounds. Furthermore, this review also explores the roles of transcription factors in macrophages, suggesting valuable insights into innovative strategies to improve tissue regeneration in chronic or pathological conditions.

Background: Lysophosphatidyl choline acyltransferase 3 (LPCAT3) is crucially involved in the remodeling of phospholipids in the membranes through incorporation of arachidonic acid (ARA; 20:4). The ARA-derived eicosanoids aggravate leukocyte adhesion, inflammation, vascular dysfunction, thrombosis, and atherogenesis. This study found that LPCAT3 modulates lipid rafts and contributes to the raft assembly/organization essential for cytokine signaling.

Methods: RNAi-dependent silencing of LPCAT3 in the endothelial cells. EPA and DHA enrichment in the cells. Lipid raft isolation and analysis of proinflammatory signaling molecules. Diet-induced atherosclerosis in the mice. LPCAT3 siRNA lipid nanoparticles/ EPA, DHA therapy.

Results: RNAi-dependent silencing of LPCAT3 inhibits TNFα-induced translocation & ubiquitination of TNFR1-signaling complex into the lipid rafts. This is associated with the attenuated NF-κB activation, synthesis of cell-adhesion molecules, cytokines, leukocyte adhesion, vascular permeability and endothelial dysfunction. Intriguingly, LPCAT3 inhibition resulted in significantly greater accretion of EPA and DHA in the PC and PE at the expense of ARA, and potentially decreased the ARA-derived eicosanoids in the vascular endothelium. Therapeutic administration of LPCAT3 siRNA-lipid nanoparticles in the high fat fed- mice markedly lowered the plasma glucose, insulin, proinflammatory cytokines, eicosanoids, and attenuated the plaque formation in the aorta. Co-treatment of LPCAT3 siRNA-lipid nanoparticles with EPA/DHA significantly elevated the accretion of EPA/DHA levels in the heart tissues and nullified the plaque development in the mice.

Conclusions: Our data revealed that LPCAT3-dependent remodeling of lipid rafts is essential for the TNF-induced signal transduction, NF-kB activation, and vascular inflammation. Administration of LPCAT3 siRNA-lipid nanoparticles and EPA/DHA is an effective strategy to combat atherosclerosis.