Inflammation Research最新文献

This correspondence comments on the recent review "Exosomes as immunomodulators in autoimmune inflammation: implications for primary Sjögren's disease," emphasizing the dual role of exosomes in primary Sjögren's disease (pSD). On one side, lymphocyte-derived vesicles contribute to epithelial dysfunction through pathogenic microRNA transfer; on the other, mesenchymal stromal cell-derived exosomes show promising immunomodulatory and regenerative properties. Salivary and tear-derived exosomes emerge as attractive diagnostic tools, although their clinical adoption remains hindered by methodological variability. The discussion extends to systemic involvement, including pulmonary hypertension and cardiovascular risk, highlighting exosomes as potential predictive biomarkers. Overall, the letter underscores the translational opportunities of exosome research in pSD while calling for advances in standardization, targeted delivery, and large-scale production to facilitate clinical integration.

Background: Traumatic spinal cord injury (SCI) is a severe clinical challenge, often leading to long-term sensory, motor, and autonomic dysfunction. The SCI cascade involves a primary physical damage phase, followed by a secondary phase of inflammatory signalling driven by microglia and other infiltrating immune cells. Immunomodulatory therapies may help promote healing and restrict secondary damage. We have previously demonstrated that interleukin (IL)-13 delivery improves functional and histopathological recovery after SCI in murine models, primarily by polarising macrophages towards an alternatively activated pro-reparative M2-like phenotype and reducing axonal contacts. Although microglia respond robustly to IL-13 in vitro, polarisation of microglia in vivo is more difficult. To better understand what conditions may restrict microglial responses to IL-13 in vivo, we sought to examine the effect of cellular context or microenvironment on IL-13 efficacy in forcing microglia polarisation in vitro.

Methods: BV2 and murine induced pluripotent stem cell (miPSC)-derived microglia were treated with IL-13 alone or in combination with lipopolysaccharide (LPS), acidic media, extracellular matrix components, high glutamate or high potassium concentrations. Following this phenotypic changes including morphology, gene/protein expression (TNFα, IL-1β, iNOS, Arg-1, CD206, F4-80) and cytokine release (TNFα) were measured using high-content screening, RT-qPCR, immunohistochemistry, and ELISA.

Results: IL-13 leads to increased expression of the anti-inflammatory marker Arg-1 while lowering expression and secretion of the pro-inflammatory markers IL-1β, iNOS, and TNFα, and expression of the microglia activation marker F4-80, signifying effective polarisation of microglia. Concomitant administration of LPS with IL-13 reduces IL-13 polarisation efficacy in microglia. Forced polarisation of microglia is also compromised by high glutamate tone, acidosis, hyperkalemia, and extracellular fibronectin, suggesting microenvironmental contexts seen in neurotrauma directly act on microglia to limit polarisation potential.

Conclusions: Our study demonstrates that the post-SCI environment dampens IL-13 efficacy on microglia. Taken together these data caution against simple immunomodulatory strategies and suggest that effective polarisation of microglia in vivo will require multimodal approaches.

Background: Long COVID is a debilitating illness with multi-systemic symptoms that affects at least 10% of individuals who have had COVID-19. Symptoms include respiratory, dermatological, gastrointestinal, cardiovascular, and most frequently reported, neurological sequelae. The most common neurological manifestations include fatigue, brain fog, memory issues, attention disorder, and headaches.

Methods: In this review, we explore the current literature and highlight key findings regarding not only the clinical presentations of neurological commitment during long COVID but mainly the mechanisms that culminate in neuroinflammation, such as autoimmunity, viral reservoirs, and lack of surveillance of T-cells.

Results: Neuroinflammation is a complex multicellular response that directly impacts microglial cells and includes inflammasome activation, trafficking of immune cells, and increased circulating autoantibodies, cytokines, and chemokines in the central nervous system, directly impacting the tissue homeostasis. This review provides important information beyond the clinical manifestations of long COVID. Here, we highlight multifactorial neuroinflammation as the main mechanism involved in long COVID, bringing together several studies that address the different mechanisms that culminate in inflammation of the central nervous system, and highlight possible biomarkers involved in this syndrome and potential therapeutic approaches that have been studied.

Conclusion: Thus, this review strengthens research into long COVID and provides new possibilities for future studies.

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.