Inflammation最新文献

Demyelination is a significant pathological feature of chronic cerebral ischemia. Recent evidence suggested that microglia played a protective role in mitigating brain ischemic injury via phagocytosis of myelin debris resulting from demyelination. Triggering receptor expressed on myeloid cells-like 2 (TREML2) is a newly discovered inflammation-associated transmembrane receptor expressed by microglia. To date, whether microglial TREML2 contributes to the phagocytosis of myelin debris in chronic cerebral ischemia has not been fully clarified. In this study, employing a bilateral carotid artery stenosis animal model and a CoCl₂-treated cellular model, we demonstrated for the first time that microglial TREML2 expression was upregulated in response to chronic cerebral ischemia. Utilizing Treml2-knockout mice, we provided the first evidence that Treml2 deficiency alleviated demyelination and cognitive deficits induced by chronic cerebral ischemia. Furthermore, this protective effect might be attributed to the microglial M2-type polarization and enhanced phagocytosis of myelin debris, both of which were induced by the Treml2 deficiency. Additionally, we showed that TREML2 regulated microglial phagocytosis of myelin debris via toll-like receptor 9 under ischemic conditions. These findings elucidated the mechanisms by which microglia modulated the phagocytosis of myelin debris in response to brain ischemic injury and suggested that inhibition of TREML2 might represent a novel therapeutic strategy for treating demyelination and cognitive decline induced by chronic cerebral ischemia.

Osteoarthritis (OA) is a degenerative joint disorder with the destruction of the joint's structural and functional which affects the entire joint. An important feature of OA is the progressive degeneration of articular cartilage due to an imbalance between extracellular matrix synthesis and degradation. While the molecular basis of OA remains unclear, microRNAs (miRNAs) have been recognized as key factors in controlling cartilage homeostasis and inflammation. Of these, miR-221 and miR-222 are implicated in inflammatory and degenerative disease, but their exact role in OA has yet to be determined. This study aims to assess the impact of miR-221/222 cluster knockout (KO) on mouse OA models and to explore its underlying mechanisms. OA was induced in miR-221/222 KO mice utilizing the destabilization of the medial meniscus (DMM) model. Joint pathology was examined by X-ray, histological scoring, immunofluorescence, and biochemical assays. In addition, in vitro studies were performed using IL-1β-treated chondrocytes. Gain-of-function experiments were performed using miR-221/222 agomir. OA tissues of mice and mouse primary chondrocytes treated with IL-1β showed a decrease in miR-221 and miR-222 expression as compared with the shamed mice. However, miR-221/222 KO mice exhibited significant osteophyte formation and cartilage degradation, with a marked increase in collagen I, MMP-13 levels, and a significant decrease in COL2A1 levels. In vitro, miR-221/222 KO led to increased inflammatory mediators like IL-6 and TNF-α, which promoted chondrocyte apoptosis and activated the MAPK signaling pathway, thereby exacerbating OA progression. Conversely, treatment with miR-221/222 agomir attenuated OA progression in vivo. These findings suggest that loss of the miR-221 cluster contributes to OA progression by promoting inflammation, apoptosis, and matrix degradation, partly through MAPK signaling. Restoring miR-221/222 may hold therapeutic potential, but human studies are needed for validation.

This study investigated the regulatory role of exosomal CD105 in macrophage polarization and its mechanisms in lupus nephritis (LN). Analysis of samples from 20 LN patients revealed significant CD105 overexpression in kidney tissues and urinary exosomes. Exosomes were isolated from the urine specimens and tested for CD105 expression levels. Exosomes overexpressing or knocking down CD105 were co-cultured with macrophages to detect the levels of M1/M2 markers (CD86, IL-6, ARG-1, and IL-10) and changes in the TGF-β1/Smad3 pathway. Rescue experiments were performed using the TGF-β1 agonist (80116-RNAH) and inhibitor (SB431542). For in vivo experiments, exosomes overexpressing or knocking down CD105 were injected into a systemic lupus erythematosus model mice (MRL/lpr) to observe changes in renal inflammation and M1 macrophage infiltration. CD105 was significantly overexpressed in LN kidney tissues and urinary exosomes. CD105 overexpression in exosomes led to a decrease in p-Smad3 levels, up-regulation of M1 markers (CD86/IL-6), and down-regulation of M2 markers (ARG-1/IL-10); on the other hand, CD105 knockdown had the opposite effect in exocytosis. 80,116-RNAH reversed the effects of CD105-induced M1 polarization. In vivo experiments confirmed that CD105 overexpression in exosomes exacerbated renal inflammation and M1 macrophage infiltration, while CD105 knockdown in exosomes attenuated renal injury. Exosomal CD105 critically drives LN progression by inducing macrophage M1 polarization through inhibition of the TGF-β1/Smad3 signaling axis. Our findings provides a new direction for the study of LN pathogenesis and the development of therapeutic targets.

MiR-181b-5p plays a critical role in the pyroptosis and injury of kidney tubular cells in diabetic kidney disease (DKD). The long noncoding RNA (lncRNA) small nucleolar RNA hostgene 7 (SNHG7) has been shown to bind to and inhibit the function of miR-181b-5p. However, the precise role of SNHG7 in DKD remains unclear. To address this, the current study measured the expression levels of SNHG7, miR-181b-5p, and Toll-like receptor 4 (TLR4) using RT-qPCR analysis of renal biopsies from both normal individuals and patients with DKD. An in vitro DKD model was subsequently established by exposing HK-2 cells to high glucose (HG). In both DKD tissues and HG-stimulated HK-2 cells, SNHG7 and TLR4 levels were significantly elevated, while miR-181b-5p levels were markedly reduced. Knockdown of SNHG7 resulted in multiple beneficial effects: it effectively attenuated high glucose-induced lactate dehydrogenase (LDH) leakage, restored cell viability, inhibited the production of inflammatory cytokines tumor necrosis factor alpha (TNF-α), interleukin 18 (IL-18), and interleukin 1β (IL-1β), and suppressed the activation of the nucleotide-binding oligomerization domain (NOD)-like receptor pyrin domain containing 3 (NLRP3)/acysteinyl aspartate-specific proteinase 1 (caspase-1)/gasdermin D (GSDMD) pathway. Mechanistically, SNHG7 functions as a molecular sponge for miR-181b-5p, while miR-181b-5p directly targets TLR4, collectively regulating nuclear factor-kappaB (NF-κB) pathway activation. Moreover, inhibition of miR-181b-5p or up-regulation of TLR4 reversed the protective effects of SNHG7 knockdown. Additionally, co-transfection of a TLR4 over-expression vector with a miR-181b-5p mimic counteracted the effects of miR-181b-5p overexpression on cell viability, LDH leakage, and the expression of inflammatory factors and pyroptosis-related molecules. In summary, SNHG7 acts as a molecular sponge for miR-181b-5p, promoting inflammation and pyroptosis in DKD, which in turn regulates TLR4 expression and the NF-κB signaling pathway.

Previous studies demonstrated that activation of the mouse G protein-coupled formyl peptide receptor 2 (mFpr2) with aspirin-triggered resolvin D1 (AT-RvD1) blocks pro-inflammatory cytokine signaling while promoting salivary gland (SG) epithelial integrity both in vitro and in vivo. In addition, mice lacking Fpr2 display alterations of SG innate and adaptive immunity. Taken together, these results indicate that Fpr2 activation with AT-RvD1 restores saliva secretion and regulates SG immunity in mice. To demonstrate the value of AT-RvD1 for use in human SG, however, we need to extend the findings above in the direction of clinical use. To this end, the current study investigated whether treatment with AT-RvD1 reduces SG inflammation and restores saliva secretion in an acute sialadenitis mouse model expressing the human formyl peptide receptor 2 (hFPR2) protein. Results indicate that mice carrying the hFPR2 and treated with lipopolysaccharide (LPS) display acute sialadenitis-like features as shown by increased levels of proliferating inflammatory cells, loss of epithelial integrity and reduced saliva secretion. In contrast, when these mice are treated with AT-RvD1, the sialadenitis-like features are drastically reduced as evidenced by a significant decrease in proliferating inflammatory cells as well as restoration of saliva secretion to levels comparable to phosphate buffered saline (PBS)-treated healthy controls. Finally, changes observed in mice carrying the hFPR2 and treated with LPS and AT-RvD1 were comparable to those observed in wild-type mice carrying the mFpr2. Together, these results demonstrate that activation of hFPR2 with AT-RvD1 resolves acute sialadenitis in vivo.

Granulomatous mastitis (GM) is a form of non-lactational breast inflammation that is closely associated with autoimmune processes, however its underlying pathogenesis remains elusive. In this study, we employed single-cell RNA sequencing (scRNA-seq) to conduct a comparative analysis of GM lesion tissues versus normal breast tissues, thereby unveiling the immune profile of GM tissues. Our investigation centered on T and NK cells, macrophages, epithelial cells, and endothelial cells. Notably, we observed a substantial infiltration of immune cells in GM tissues, accompanied by immune disorders, an elevation in Th1 cell counts, enrichment of the toll-like receptor (TLR) pathway, and upregulation of various factors including interferon-γ (IFN-γ), C-C motif chemokine ligand 3 (CCL3), CCL4, chemokine (C-X-C motif) ligand (CXCL) 13, CD69, signal transducer and activator of transcription 1 (STAT1), and heat shock protein family A member 1A (HSPA1A). Furthermore, the macrophage subpopulations in GM tissues exhibited a transition to a pro-inflammatory phenotype, enriched for pathways such as interferon-γ (IFN-γ), IFN-α, interleukin-6/janus kinase/signal transducer and activator of transcription 3 (IL-6/JAK/STAT3), and tumor necrosis factor-α/nuclear factor-κB (TNF-α/NF-κB). Mammary luminal cells demonstrated an impaired estrogenic profile yet displayed upregulation of prolactin downstream signaling pathways, namely the JAK/STAT and mitogen-activated protein kinase (MAPK) pathways. Additionally, vascular endothelial cells were found to recruit immune cells and exhibited a prominent angiogenic profile in GM tissues. Cellular interaction analysis unveiled an intricate network of interactions between mesenchymal and immune cells. This study provides a comprehensive immune landscape of granulomatous mastitis and offers some potential therapeutic targets for the disease.