Inflammation Research最新文献

Alternatively activated macrophage (M2) polarization can result in one of four subtypes based on cytokines and signaling pathways associated with macrophage activation: M2a, M2b, M2c, and M2d macrophages. The majority of M2 subtypes are anti-inflammatory and pro-angiogenic, secreting growth factors (VEGF, PDGF) and matrix metalloproteinases (MMP2, MMP9) which boost tumor growth, metastasis, and invasion. M2-polarized macrophages are associated with immune suppressor cells harboring Myeloid derived suppressor cells, Regulatory T cells (Tregs), Regulatory B cells as well as alternatively activated (N2) neutrophils. Treg cells selectively support the metabolic stability, mitochondrial integrity, and survival rate of M2-like TAMs in an indirect environment. Also, the contribution of Breg cells influences macrophage polarization towards the M2 direction. TAM is activated when TAN levels in the tumor microenvironment are insufficient or vice versa, suggesting that macrophage and its polarization are fine-tuned. Understanding the functions of immune suppressive cells, mediators, and signaling pathways involved with M2 polarization will allow us to identify potential strategies for targeting the TAM repolarization phenotype for innovative immunotherapy approaches. In this review, we have highlighted the critical factors for M2 macrophage polarization, differential cytokine/chemokine profiles of M1 and M2 macrophage subtypes, and other immune cells' impact on the polarization within the immunosuppressive niche.

Objective and design: The exact immunological mechanism of widespread chronic inflammatory skin disorder psoriasis has not been fully established. CD11b⁺Gr.1⁺ myeloid-derived cells are immature heterogeneous cells with T-cell suppressive property in neoplasia; however, influence of these cells on adaptive immunity is highly contextual; therefore, we dubbed these cells as myeloid-derived adjuster cells (MDAC). We studied imiquimod induced psoriasis in mouse model and evaluated for the first time the RORγt-NFAT1 axis in MDACs and the function, differentiation and interaction of these cells with T cells.

Materials and methods: The status of T cells and MDACs; their functionality and differentiation properties, and the roles of RORγt and NFAT1 in MDACs were evaluated using flow cytometry, qRT-PCR and confocal imaging.

Results: We found gradual increase in T cells and MDACs and an increase in the number of IL17 -secreting MDACs and T cells in the skin of psoriatic animals. We also noted that MDAC differentiation is biased toward M1 macrophages and DCs which perpetuate inflammation. We found that psoriatic MDACs were unable to suppress T-cell proliferation or activation but seemingly helped these T cells produce more IL17. Inhibition of the RORγt/NFAT1 axis in MDACs increased the suppressive nature of MDACs, allowing these cells to suppress the activity of psoriatic T-cells.

Conclusion: Our results indicate that altered MDAC properties in psoriatic condition sustains pathological inflammation and RORγt and NFAT1 as promising intervention target for psoriasis management.

Background: Microglia, the main innate immune cells in the central nervous system, are key drivers of neuroinflammation, which plays a crucial role in the pathogenesis of neurodegenerative diseases. The Sin3/histone deacetylase (HDAC) complex, a highly conserved multiprotein co-repressor complex, primarily performs transcriptional repression via deacetylase activity; however, the function of SDS3, which maintains the integrity of the complex, in microglia remains unclear.

Methods: To uncover the regulatory role of the transcriptional co-repressor SDS3 in microglial inflammation, we used chromatin immunoprecipitation to identify SDS3 target genes and combined with transcriptomics and proteomics analysis to explore expression changes in cells following SDS3 knocking down. Subsequently, we validated our findings through experimental assays.

Results: Our analysis revealed that SDS3 modulates the expression of the upstream kinase ASK1 of the p38 MAPK pathway, thus regulating the activation of signaling pathways and ultimately influencing inflammation.

Conclusions: Our findings provide important evidence of the contributions of SDS3 toward microglial inflammation and offer new insights into the regulatory mechanisms of microglial inflammatory responses.

Objective: A coagulation factor called fibrinogen is produced by the liver and is proteolyzed by thrombin to become fibrin. The latest studies have revealed that fibrin(ogen) palys an essential role in the regulation of cardiovascular disease. Understanding the relationship and mechanism between fibrin(ogen) and cardiovascular disease is of great significance for maintaining overall health. The objective of this review is to discuss the specific involvement and underlying mechanisms of fibrin(ogen) in cardiovascular disease.

Methods: A review was conducted using the PubMed database to identify and analyze the emerging role of fibrinogen in cardiovascular disease.

Results: The literature review revealed that fibrin(ogen) plays a pivotal role in maintaining cardiovascular disease and are involved in the pathogenesis of cardiovascular disease. Fibrin(ogen) mainly influence various pathophysiological processes, such as participating in thrombosis formation, stimulating the inflammatory response, and other molecular pathways.

Conclusion: This review focuses on the involvement of fibrin(ogen) in cardiovascular disease, with a particular emphasis on the main functions and underlying mechanisms by which fibrin(ogen) influence the pathogenesis and progression of these conditions. This review underscores the potential of fibrin(ogen) as therapeutic targets in managing cardiovascular disease.

Background: Neuroblastoma (NB) is the most prevalent and deadliest pediatric solid tumor. With of over 50% of high-risk neuroblastoma cases relapse, the imperative for novel drug targets and therapeutic strategies is accentuated. In neuroblastoma, the existence of tumor-associated macrophages (TAMs) correlates with an unfavorable patient prognosis. However, the clinical relevance and prognostic implications of regulatory genes linked to TAMs infiltration in neuroblastoma remain unclear, and further study is required.

Methods: We conducted a comprehensive analysis utilizing transcriptome expression profiles from three primary datasets associated with neuroblastoma (GSE45547, GSE49710, TARGET) to identify hub genes implicated in immune evasion within neuroblastoma. Subsequently, we utilized single-cell RNA sequencing analysis on 17 clinical neuroblastoma samples to investigate the expression and distribution of these hub genes, leading to the identification of TNFAIP3. The above three public databases were merged to allowed for the validation of TNFAIP3's molecular functions through GO and KEGG analysis. Furthermore, we assessed TNFAIP3's correlation with immune infiltration and its potential immunotherapeutic impact by multiple algorithms. Our single-cell transcriptome data revealed the role of TNFAIP3 in macrophage polarization. Finally, preliminary experimental verifications to confirm the biological functions of TNFAIP3-mediated TAMs in NB.

Results: A total of 6 genes related to immune evasion were screened and we found that TNFAIP3 exhibited notably higher expression in macrophages than other immune cell types, based on the scRNA-sequencing data. GO and KEGG analysis showed that low expression of TNFAIP3 significantly correlated with the activation of multiple oncogenic pathways as well as immune-related pathways. Then validation affirmed that individuals within the TNFAIP3 high-expression cohort could potentially derive greater advantages from immunotherapeutic interventions, alongside exhibiting heightened immune responsiveness. Deciphering the pseudotime trajectory of macrophages, we revealed the potential of TNFAIP3 in inducing the polarization of macrophages towards the M1 phenotype. Finally, we confirmed that patients in the TNFAIP3 high expression group might benefit more from immunotherapy or chemotherapy as substantiated by RT-qPCR and immunofluorescence examinations. Moreover, the role of TNFAIP3 in macrophage polarization was validated. Preliminary experiment showed that TNFAIP3-mediated TAMs inhibit the proliferation, migration and invasion capabilities of NB cells.

Conclusions: Our results suggest that TNFAIP3 was first identified as a promising biomarker for immunotherapy and potential molecular target in NB. Besides, the presence of TNFAIP3 within TAMs may offer a novel therapeutic strategy for NB.

Objective: We aimed to broaden our understanding of a potential interaction between B1R and TLR4, considering earlier studies suggesting that lipopolysaccharide (LPS) may trigger B1R stimulation.

Methods: We assessed the impact of DBK and LPS on the membrane potential of thoracic aortas from C57BL/6, B1R, or TLR4 knockout mice. Additionally, we examined the staining patterns of these receptors in the thoracic aortas of C57BL/6 and in endothelial cells (HBMEC).

Results: DBK does not affect the resting membrane potential of aortic rings in C57BL/6 mice, but it hyperpolarizes preparations in B₁KO and TLR4KO mice. The hyperpolarization mechanism in B₁KO mice involves B2R, and the TLR4KO response is independent of cytoplasmic calcium influx but relies on potassium channels. Conversely, LPS hyperpolarizes thoracic aorta rings in both C57BL/6 and B₁KO mice, with the response unaffected by a B1R antagonist. Interestingly, the absence of B1R alters the LPS response to potassium channels. These activities are independent of nitric oxide synthase (NOS). While exposure to DBK and LPS does not alter B1R and TLR4 mRNA expression, treatment with these agonists increases B1R staining in endothelial cells of thoracic aortic rings and modifies the staining pattern of B1R and TLR4 in endothelial cells. Proximity ligation assay suggests a interaction between the receptors.

Conclusion: Our findings provide additional support for a putative connection between B1R and TLR4 signaling. Given the involvement of these receptors and their agonists in inflammation, it suggests that drugs and therapies targeting their effects could be promising therapeutic avenues worth exploring.

Background: Invariant natural killer T (iNKT) cells play protective or pathogenic roles in a variety of immune and inflammatory diseases. However, whether iNKT cells contribute to the progression of acute neuroinflammation remains unclear. Thus, we addressed this question with a mouse model of lipopolysaccharide (LPS)-induced acute neuroinflammation.

Methods: For induction of acute neuroinflammation, wild-type (WT) C57BL/6 (B6) mice were injected intraperitoneally (i.p.) with LPS for either three or five consecutive days, and then these mice were analyzed for brain-infiltrating leukocytes or mouse behaviors, respectively. To examine the role of iNKT cell activation in LPS-induced neuroinflammation, mice were injected i.p. with the iNKT cell agonist α-galactosylceramide (α-GalCer) seven days prior to LPS treatment. Immune cells infiltrated into the brain during LPS-induced neuroinflammation were determined by flow cytometry. In addition, LPS-induced clinical behavior symptoms such as depressive-like behavior and memory impairment in mice were evaluated by the open field and Y-maze tests, respectively.

Results: We found that iNKT cell-deficient Jα18 mutant mice display delayed disease progression and decreased leukocyte infiltration into the brain compared with WT mice, indicating that iNKT cells contribute to the pathogenesis of LPS-induced neuroinflammation. Since it has been reported that pre-treatment with α-GalCer, an iNKT cell agonist, can convert iNKT cells towards anti-inflammatory phenotypes, we next explored whether pre-activation of iNKT cells with α-GalCer can regulate LPS-induced neuroinflammation. Strikingly, we found that α-GalCer pre-treatment significantly delays the onset of clinical symptoms, including depression-like behavior and memory impairment, while decreasing brain infiltration of pro-inflammatory natural killer cells and neutrophils, in this model of LPS-induced neuroinflammation. Such anti-inflammatory effects of α-GalCer pre-treatment closely correlated with iNKT cell polarization towards IL4- and IL10-producing phenotypes. Furthermore, α-GalCer pre-treatment restored the expression of suppressive markers on brain regulatory T cells during LPS-induced neuroinflammation.

Conclusion: Our findings provide strong evidence that α-GalCer-induced pre-activation of iNKT cells expands iNKT10 cells, mitigating depressive-like behaviors and brain infiltration of inflammatory immune cells induced by LPS-induced acute neuroinflammation. Thus, we suggest the prophylactic potential of iNKT cells and α-GalCer against acute neuroinflammation.

Objective: Systemic inflammation is associated with improper localization of hyperactive neutrophils and monocytes in visceral organs. Previously, a C-terminal fragment of adhesion protein Fibulin7 (Fbln7-C) was shown to regulate innate immune functionality during inflammation. Recently, a shorter bioactive peptide of Fbln7-C, FC-10, via integrin binding was shown to reduce ocular angiogenesis. However, the role of FC-10 in regulating the neutrophils and monocyte functionality during systemic inflammatory conditions is unknown. The study sought to explore the role of FC-10 peptide on the functionality of innate immune cells during inflammation and endotoxemic mice.

Methods: Neutrophils and monocytes were isolated from healthy donors and septic patient clinical samples and Cell adhesion assay was performed using a UV spectrophotometer. Gene expression studies were performed using qPCR. Protein level expression was measured using ELISA and flow cytometry. ROS assay, and activation markers analysis in vitro, and in vivo were done using flow cytometry.

Treatment: Cells were stimulated with LPS (100 ng/mL) and studied in the presence of peptides (10 μg, and 20 μg/mL) in vitro. In an in vivo study, mice were administered with LPS (36.8 mg/kg bw) and peptide (20 μg).

Results: This study demonstrates that human neutrophils and monocytes adhere to FC-10 via integrin β1, inhibit spreading, ROS, surface activation markers (CD44, CD69), phosphorylated Src kinase, pro-inflammatory genes, and protein expression, compared to scrambled peptide in cells isolated from healthy donors and clinical sample. In line with the in vitro data, FC-10 (20 μg) administration significantly decreases innate cell infiltration at inflammatory sites, improves survival in endotoxemia animals & reduces the inflammatory properties of neutrophils and monocytes isolated from septic patients.

Conclusion: FC-10 peptide can regulate neutrophils and monocyte functions and has potential to be used as an immunomodulatory therapeutic in inflammatory diseases.

Objectives: Sepsis is a systemic inflammatory disorder characterized by life-threateningorgan dysfunction resulting from a dysregulated host response to infection. Prostacyclin (PGI₂) is a bioactive lipid produced by PGI synthase (PGIS) and is known to play important roles in inflammatory reactions as well as cardiovascular regulation. However, little is known about the roles of PGIS and PGI₂ in systemic inflammatory responses such as septic shock.

Methodology: Systemic inflammation was induced by intraperitoneal injection of 5 mg/kg lipopolysaccharide (LPS) in wild type (WT) or PGIS knockout (KO) mice. Selexipag, a selective PGI₂ receptor (IP) agonist, was administered 2 h before LPS injection and again given every 12 h for 3 days.

Results: Intraperitoneal injection of LPS induced diarrhea, shivering and hypothermia. These symptoms were more severe in PGIS KO mice than in WT micqe. The expression of Tnf and Il6 genes was notably increased in PGIS KO mice. In contrast, over 95% of WT mice survived 72 h after the administration of LPS, whereas all of the PGIS KO mice had succumbed by that time. The mortality rate of LPS-administrated PGIS KO mice was improved by selexipag administration.

Conclusion: Our study suggests that PGIS-derived PGI₂ negatively regulates LPS-induced symptoms via the IP receptor. PGIS-derived PGI₂-IP signaling axis may be a new drug target for systemic inflammation in septic shock.