Inflammation Research最新文献

Itaconate, a mitochondrial metabolite generated from cis-aconitate via IRG1 (ACOD1), has emerged as a key immunometabolic signal that links metabolic reprogramming with immune regulation. Beyond its origin in the tricarboxylic acid (TCA) cycle, itaconate exemplifies how metabolic intermediates can reshape cell fate and function under stress and inflammation. Upon inflammatory stimulation, immune cells-particularly macrophages-undergo profound metabolic rewiring. Itaconate orchestrates this shift by inhibiting succinate dehydrogenase (SDH), accumulating succinate, activating nuclear factor erythroid 2-related factor 2 (Nrf2)-mediated antioxidant responses, and modulating glycolytic flux, thus balancing inflammatory output and oxidative stress. This review provides an integrative overview of itaconate biosynthesis, metabolic regulation, and functional mechanisms across diverse physiological and pathological contexts. Itaconate and its derivatives, such as 4-octyl itaconate (4-OI), exhibit promising effects in preclinical models of sepsis, acute lung injury, autoimmune diseases (e.g., SLE and RA), ischemia-reperfusion injury, infection (bacterial and viral), and cancer. These effects are closely linked to itaconate's capacity to reprogram immune metabolism and modulate signaling pathways such as NF-κB, NLRP3, and JAK/STAT. Importantly, recent findings suggest that itaconate not only modulates inflammation but also affects immune cell death pathways, ferroptosis susceptibility, and tumor immune evasion. These multifaceted roles make itaconate a potential metabolic checkpoint in the development of new therapeutic strategies. However, challenges such as metabolic instability, limited bioavailability, and potential off-target effects remain to be addressed. In summary, itaconate represents a powerful endogenous modulator of immunometabolism. Its therapeutic utility, as a direct drug, as a scaffold for derivative design, or as a biomarker for inflammation resolution, holds significant promise for treating inflammation-driven diseases through the lens of metabolic reprogramming. This review summarizes itaconate biosynthesis, its molecular mechanisms in health and disease, and recent advances across multiple conditions, providing a foundation for future immunometabolic therapies.

Background: Sepsis is a global health problem that ends millions of lives and costs billions of dollars in treatment and management every year. This disease is responsible for one in every five deaths worldwide, and is the third leading cause of death in hospitals. Despite decades of research, no current specific treatment or cure are available, only supportive and symptomatic care, and few preclinical studies reach human trials. Since the discovery of the endocannabinoid system (ECS), cannabinoids have been researched as a potential treatment for various diseases, including sepsis. Our review aimed to summarize what is known about the endocannabinoid system research in preclinical sepsis.

Methods: A scoping search was conducted in the databases Pubmed, Scopus and Web of Science. Articles were selected in case they studied a cannabinoid or the ECS in preclinical sepsis or septic shock, with no time limit. Data regarding animals species, model os sepsis, treatments, cannabinoids utilized and main outcomes were analyzed.

Results: We found that the most commonly used animal species was both Mus musculus and Rattus norvegicus, and the most frequently performed sepsis model was the endotoxemia induced by lipopolysaccharide (LPS). The most studied receptor was cannabinoid receptor type 2 (CB2) and among all cannabinoid types, synthetic cannabinoids were researched in the majority of the studies. We also discuss the evaluated outcomes, as well as their involvement with the endocannabinoid system and underlying molecular mechanisms. We highlight the main promising results and explore the limitations and future challenges in the field.

Conclusion: Cannabinoids are promising therapeutic targets in the treatment of sepsis, as they improved survival, and reduced inflammation and organ injury. However, deleterious adverse effects were reported, with the underlying molecular mechanisms still unknown, and further research is needed to evaluate their benefits and future use in clinical research.

Although aspirin is one of the best characterized drugs for the therapeutic effects on coagulation and inflammation, there are clues that it may also have a significant impact on cancer immunity. In this study, IFNg, a pro-inflammatory cytokine, has been demonstrated to increase the protein expression of PD-L1 in non-small cell lung carcinoma cells. In the molecular modeling of stimulated and/or aspirin-treated cancer secretome and macrophage interaction, CD38 (M1 macrophage marker) and CD209 (M2 macrophage marker) expressions confirmed that peripheral blood mononuclear cells differentiated into M1 or M2 macrophages afterwards polarization. Transcriptomic profiling was performed after 48 h of culture with differentiated M2-polarized macrophages in the presence of lung cancer cell secretomes. In contrast to the EGFR mutant aspirin-treated HCC827 cell line, the findings revealed that factors produced by the non-EGFR mutant aspirin-treated IFNg-induced H838 cancer cell secretome can alter M2 macrophage dynamics. Furthermore, significant patterns were obtained in gene expression profiles related to "Hematopoietic Cell Lineage" and "Antigen Processing and Presentation" between groups in M2-polarized macrophages established with these secretomes. However, aspirin treatment had different effects on cancer cell lines that expressed endogenous and induced PD-L1. As a result, flow cytometry analysis demonstrated that administering aspirin to HCC827 cancer cells boosted the expression of PD-L1 on their surface. Analysis of EGFR mutations, aspirin resistance, and PD-L1 levels, as well as M2 macrophage infiltration in the non-small cell lung cancer microenvironment and immune phenotyping of M2 macrophage subtypes, will assist in developing lung cancer therapy approaches that combine EGFR inhibitors and aspirin.

Objective: Xiaoqinglong Decoction (XQLD) is a traditional oriental medicine. Modified- Xiaoqinglong Decoction (M-XQLD) was established by adding astragalus membranaceus and codonopsis pilosula on the basis of XQLD. M-XQLD has been shown to be effective in therapying asthma in clinical trials, but the mechanism of M-XQLD in asthma is currently unknown.

Methods: Mice were sensitized by ovalbumin (OVA) to induce asthma. M-XQLD were administered by oral gavage. Label-free proteomics was conducted to identify the downstream target of M-XQLD. Histopathological assessment, multiple cytokine examination in bronchoalveolar lavage fluid (BALF) were conducted. In vitro, we isolated Naïve CD4 + T cells for analysis.

Results: OVA stimulation decreased the expression of StAR Related Lipid Transfer Domain Containing 13 (STARD13), while M-XQLD treatment increased it. STARD13 overexpression reduced the inflammatory cell infiltration and goblet cells. STARD13 overexpression reduced the levels of OVA-specific IgE, IL-4, and IL-5 in serum and BALF. STARD13 overexpression inhibited the expression of IL-1β, IL-17A, and IL-22, and reduced Th17 differentiation. STARD13 overexpression inhibited the RhoA/ROCK2, while knockdown of STARD13 resulted in continuous activation of RhoA. Furthermore, STARD13 overexpression decreased p38 phosphorylation level. SB203580 treatment further inhibited the RORC expression and p38 phosphorylation. More importantly, the therapeutic efficacy of M-XQLD in OVA-induced mice was significantly reduced by STARD13 knockdown.

Conclusions: This study revealed that M-XQLD targets to STARD13, and highlighted that STARD13 alleviated asthma by reducing Th17 differentiation via inhibiting the RhoA/ROCK2/p38 signaling.

Background: Tuberculosis (TB) is a major infectious disease that can lead to systemic complications, including osteoporosis, particularly in immunocompromised individuals. Exosomal miRNAs derived from TB-infected macrophages have been implicated in various pathophysiological processes, including bone metabolism. This study investigates how exosomal miR-125b-5p from TB-infected macrophages contributes to osteoporosis by targeting insulin-like growth factor 2 (IGF2) and modulating the PI3K/AKT signaling pathway.

Methods: We analyzed NHANES data to compare bone mineral density in TB patients and healthy controls. In vitro experiments were conducted with Mycobacterium tuberculosis-infected peritoneal macrophages from C57BL/6 mice, isolating exosomes and using Western blot, flow cytometry, and bioinformatics tools to assess the role of miR-125b-5p in regulating osteogenic markers. In vivo studies in mouse models were performed to evaluate the impact of exosomal miR-125b-5p on bone density and structure.

Results: Exosomes from TB-infected macrophages were found to contain elevated levels of miR-125b-5p, which targeted IGF2 and inhibited the PI3K/AKT pathway, leading to impaired osteoblast function and reduced bone formation. Knockdown of miR-125b-5p partially restored osteogenic markers and bone density. Furthermore, IGF2 silencing exacerbated bone loss, confirming the critical role of IGF2 in TB-induced osteoporosis.

Conclusion: This study demonstrates that miR-125b-5p from TB-infected macrophages promotes osteoporosis by disrupting the IGF2/PI3K/AKT signaling axis. Targeting this pathway could provide a potential therapeutic strategy for managing TB-induced osteoporosis. Further clinical studies are necessary to validate these findings and explore additional therapeutic options.

Objective and design: Investigate the potential role of histamine and its receptors on the functional expression of the sodium/hydrogen (Na⁺/H⁺) exchanger (NHE)3.

Material: The human epithelial kidney (HK-2) cells were used as an in vitro model of the renal proximal tubule.

Treatment: HK-2 cells were exposed to histamine 0-1000 nM alone or in combination with chlorphenamine (10 μM) and JNJ-7777120 (1 μM) for 0-48 h. MAPK involvement was determined using the selective inhibitors SB202190 (p38 MAPK), PD98059 (ERK1/2), and SP600125 (SAPK/JNK).

Methods: Gene and protein expression were evaluated by qPCR and immunoblotting. The activity of NHE3 was measured by the BCECF-AM-based method.

Results: Histamine (100 nM) induced a concentration-dependent NHE3 gene transcription with a peak 16 h after the treatment, followed by protein translation at 48 h after. A Consistent increase in NHE3 activity was observed at 48 h, but also at 60 min, when both p38 MAPK and ERK1/2 were phosphorylated. JNJ-7777120 blunted the activation and expression of NHE3. Chlorpheniramine was effective only on NHE3 activity.

Conclusions: Histamine shows early (within 60 min) and late (48 h) effects on NHE3 expression. The histamine H₁ and H₄ receptors are shown to contribute to these effects differentially. The findings of this study extends the evidence for a direct contribution of histamine on the renal reabsorptive machinery.

Background: The roles of long non-coding RNAs (lncRNAs) in the progression of various human tumors have been extensively studied. However, their specific mechanisms and therapeutic potential in Triple-Negative Breast Cancer (TNBC) remain to be fully elucidated.

Materials and methods: The qRT-PCR assay was utilized to assess the relative mRNA levels of TFAP2A-AS1, PHGDH, and miR-6892. To investigate the impact of TFAP2A-AS1, we conducted various assays, including CCK-8, Transwell, flow cytometry, and clonal formation assays, to analyze cell viability, invasion, apoptosis, and proliferation capabilities of TNBC cells. Additionally, the effects of TFAP2A-AS1 on tumor growth were evaluated through in vivo xenograft models. To explore and confirm the interactions between TFAP2A-AS1 and miR-6892, as well as between miR-6892 and PHGDH, we employed bioinformatics analysis and dual-luciferase reporter assays. Lastly, Western blot analysis and immunohistochemistry (IHC) were performed to determine the protein expression levels of PHGDH and EMT-related markers in treated TNBC cells and xenograft tissues.

Results: Our study revealed that TFAP2A-AS1 was notably downregulated in TNBC cell lines, whereas PHGDH was upregulated. High PHGDH expression correlated with poorer survival outcomes, suggesting its oncogenic role in TNBC. Functional assays demonstrated that overexpression of TFAP2A-AS1 suppressed proliferation, clonal formation, migration, and invasion, while promoting apoptosis in TNBC cells. Conversely, overexpression of PHGDH had the opposite effects, promoting tumorigenic traits. Mechanistically, TFAP2A-AS1 was found to act as a sponge for miR-6892, thereby upregulating its expression and subsequently inhibiting the target gene PHGDH. In vivo experiments confirmed that TFAP2A-AS1 overexpression inhibited tumor growth, an effect that was partially reversed by the inhibition of miR-6892 or overexpression of PHGDH.

Conclusion: Our study demonstrates that lncRNA TFAP2A-AS1 inhibits TNBC progression by modulating the miR-6892/PHGDH axis. These findings reveal that TFAP2A-AS1 suppresses key malignant characteristics of TNBC, such as proliferation, migration, and invasion. These insights suggest that targeting this pathway could offer a potential therapeutic strategy for TNBC, a subtype known for its limited targeted treatment options.

Cardiovascular diseases (CVDs) are a group of conditions that significantly affect human health and are among the leading causes of death and disability worldwide. Clinical trials and basic research have demonstrated that inflammation plays a pivotal role in the development of CVDs. The inflammasome is a critical component of the innate immune system, involved in various inflammatory responses to pathogens and tissue damage. Absent in melanoma2(AIM2), which belongs to the PYHIN Family, is a receptor for intracellular DNA pattern recognition. AIM2 inflammasomes are implicated in the onset and progression of CVDs, activated in atherosclerotic plaques, aortic aneurysms, and damaged myocardium. This review summarizes recent advances in AIM2 research in CVDs, exploring its interactions with other inflammasomes and emphasizing its central role in immune and inflammatory responses. Specifically, the review summarizes the progress of AIM2 inhibitors, in order to critically evaluate the translational potential of such concepts into clinical practices.

Background: Sepsis-Associated Encephalopathy (SAE) is a severe neurological complication of sepsis, where neuroinflammation plays a critical pathogenic role, leading to cognitive dysfunction. The Sigma-1 receptor (Sigma-1R), a chaperone protein, is implicated in neuroprotection, including the crucial modulation of neuroinflammation and endoplasmic reticulum stress (ERS). This study aimed to investigate the therapeutic potential of the Sigma-1R agonist, PRE-084, in specifically targeting SAE-associated neuroinflammation and its downstream neuropathology.

Methods: A cecal ligation and puncture (CLP) murine model of sepsis was established. Mice received the Sigma-1R agonist PRE-084 or saline. Neurological function (SHIRPA), survival rates, and cognitive performance (Morris Water Maze) were assessed. Hippocampal and cortical tissues were analyzed for Sigma-1R expression and localization, ERS markers (BiP, p-eIF2α), synaptic protein levels (PSD95, Synaptophysin), glial cell activation (Iba-1, GFAP), pro-inflammatory cytokine levels (TNF-α, IL-6), and p38 Mitogen-Activated Protein Kinase (p38 MAPK) pathway activation using Western blotting, immunofluorescence, and ELISA.

Result: CLP surgery induced neurological deficits, reduced survival, and upregulated neuronal Sigma-1R in the hippocampus. PRE-084 administration significantly improved survival rates, ameliorated neurological impairments, and attenuated cognitive dysfunction in CLP mice. Mechanistically, PRE-084 treatment directly mitigated neuronal CLP-induced ERS (reduced BiP expression and eIF2α phosphorylation) and preserved hippocampal postsynaptic density protein 95 (PSD95) levels. Crucially, these primary neuroprotective effects on neurons translated into a profound suppression of neuroinflammation, evidenced by reduced microglial (Iba-1) and astrocyte (GFAP) activation, decreased brain levels of pro-inflammatory cytokines TNF-α and IL-6, and specific inhibition of microglial p38 MAPK activation. This indicates an indirect but potent anti-inflammatory effect stemming from primary neuronal Sigma-1R engagement.

Conclusion: Our findings demonstrate that activation of neuronal Sigma-1R by PRE-084 confers protection against SAE. This protection involves primary mitigation of neuronal ERS, which is pivotal in subsequently dampening the detrimental microglial p38 MAPK-mediated neuroinflammatory cascade. This multifaceted action, culminating in reduced neuroinflammation, improves neurological outcomes and cognitive function. Targeting Sigma-1R to control neuroinflammation offers a promising therapeutic strategy for SAE.