Inflammation and regeneration最新文献

During human evolution, some genes were lost or silenced from the genome of hominins. These missing genes might be the key to the evolution of humans' unique cognitive skills. An inactivation mutation in CMP-N-acetylneuraminic acid hydroxylase (CMAH) was the result of natural selection. The inactivation of CMAH protected our ancestors from some pathogens and reduced the level of N-glycolylneuraminic acid (Neu5Gc) in brain tissue. Interestingly, the low level of Neu5Gc promoted the development of brain tissue, which may have played a role in human evolution. As a xenoantigen, Neu5Gc may have been involved in brain evolution by affecting neural conduction, neuronal development, and aging.

Background: Recent evidence suggests that clonally expanded cytotoxic T cells play a role in various autoimmune diseases. Late-onset rheumatoid arthritis (LORA) exhibits unique characteristics compared to other RA forms, suggesting distinct immunological mechanisms. This study aimed to examine the involvement of cytotoxic T cells in LORA.

Methods: Fresh peripheral blood samples were collected from 78 treatment-naïve active RA patients, 12 with difficult-to-treat RA, and 16 healthy controls. Flow cytometry was employed to measure the proportions of CX3CR1⁺cytotoxic CD4⁺ and CD8⁺ T cells in these samples. Additionally, immunohistochemical staining was performed on lymphoid node and synovial biopsy samples from patients with RA.

Results: CX3CR1⁺cytotoxic CD4⁺ T cells were specifically increased in untreated, active patients with LORA, displaying features of CXCR3^mid age-associated T helper cells known as "ThA". CX3CR1⁺CD4⁺ T cells were identified as a cytotoxic ThA subset, as nearly all of these cells specifically expressed granzyme B. These cells were observed in enlarged lymph nodes and were found to infiltrate synovial tissues from patients with LORA. The proportions of CX3CR1⁺CD4⁺ T cells positively correlated with arthritis activity in LORA. The number of cells decreased after treatment with methotrexate, tumor necrosis factor inhibitors, and interleukin-6 inhibitors, whereas T-cell activation modulators did not affect them. Moreover, PD-1⁺CD38⁺CX3CR1⁺CD4⁺ T cells were identified as a treatment-resistant T cell subset that was characteristically increased in difficult-to-treat RA. CX3CR1⁺CD8⁺ T cells showed no significant difference between RA patients and healthy individuals, and no correlation with disease activity was observed. However, a correlation with age was observed in RA patients.

Conclusions: Our findings suggest that the immunopathogenesis of RA differs by age of onset, with CX3CR1⁺ age-associated cytotoxic CD4⁺ T cells playing a significant role in LORA. Additionally, the presence of a specific CX3CR1⁺ T cell subset may be linked to treatment resistance.

Background: The incidence of periodontitis is high in older individuals. However, its impact on multi-organ frailty remains unclear. We developed mouse models with varying severity and duration of periodontitis to examine its effects.

Methods: We generated mouse models with mild and severe periodontitis, categorizing the disease duration into 3-month and 5-month periods for analysis. The organs assessed for frailty included the gastrocnemius muscle, soleus muscle, brain, and femur.

Results: Our study found that periodontitis induced systemic inflammation resembling inflammaging and other symptoms characteristic of age-induced frailty. Notably, muscle impairment developed specifically in slow-twitch muscles, and the femur emerged as the most vulnerable bone, exhibiting reduced bone mineral density even with mild and short-duration periodontitis. This condition resulted in the co-occurrence of bone fragility and slow-twitch muscle dysfunction. Cognitive function assessment revealed increased activated microglia and decreased adult neurogenesis in the hippocampus, impairing spatial learning. Thus, periodontitis induced both physical and cognitive frailties. Therapeutic intervention for the periodontitis, which halted the exacerbation of bone resorption markers, did not restore femur bone mineral density.

Conclusion: This study underscores the role of periodontitis in inducing multifaceted organ frailty with vulnerability, varying by organ, and the necessity of early intervention, particularly regarding bone density loss.

Background: For the treatment of liver fibrosis, several novel cell therapies have been proposed. Autologous macrophage therapy has been reported as one of the promising treatments. So far, most studies have used colony-stimulating factor 1 (CSF-1) to induce the differentiation of macrophage progenitor cells. The receptor for CSF-1, CSF-1R possesses another ligand, interleukin 34. However, the therapeutic capacity for liver fibrosis by interleukin 34-induced macrophages has not been evaluated.

Methods: We have employed acute (bile duct ligation) and chronic (administration of carbon tetrachloride or thioacetamide) liver fibrosis models. Using these models, we evaluated the therapeutic capacity of macrophages induced by interleukin 34-based conditions. In most experiments, interleukin 4 was also added to the differentiation process to induce alternative-activated macrophages. As a mechanism analysis, we have examined liver inflammation and damage, the status of stellate cells, and the immunosuppressive capacity of the macrophages. Human macrophages were differentiated from CD14⁺ monocytes and analyzed.

Results: In both acute and chronic liver damage experiments, interleukin 34-induced macrophages significantly ameliorated liver fibrosis. The addition of interleukin 4 to the differentiation process resulted in an increase of obtained macrophages and a bias to alternative activated macrophages (so-called M2). The alternative activated macrophages (M2-type) showed a reproducible therapeutic effect of liver fibrosis with a suppression of parameters of liver inflammation and damage, stellate cells, and T cell activation. Similar macrophages could be differentiated from human CD14⁺ monocytes in the presence of interleukin 34 plus interleukin 4, and a therapeutic effect was observed using a humanized mouse model.

Conclusions: Interleukin 34-induced macrophages, particularly when additionally stimulated with interleukin 4, significantly ameliorated the liver fibrosis.

Idiopathic inflammatory myopathies (IIMs) are a group of autoimmune disorders characterized by immune cell infiltration of muscle tissue accompanied by inflammation. Treatment of IIMs is challenging, with few effective therapeutic options due to the lack of appropriate models that successfully recapitulate the features of IIMs observed in humans. In the present study, we demonstrate that immunodeficient mice transplanted with human peripheral blood mononuclear cells (hPBMCs) exhibit the key pathologic features of myositis observed in humans and develop graft-versus-host disease. The hPBMC mice exhibit elevated serum levels of creatine kinase and aspartate transaminase, markers of myositis, and increased expression levels of myositis-related genes, such as vascular cell adhesion molecule 1, intercellular adhesion molecule 1, and serum amyloid A1, in muscle tissues. Histopathologic and flow cytometric analyses reveal the infiltration of CD8⁺ T cells in the muscle tissue of hPBMC mice, similar to that observed in patients with myositis, particularly in those with polymyositis. Transplantation of CD8⁺ T cell-depleted hPBMC leads to a significant reduction in polymyositis-like symptoms, in agreement with previous studies demonstrating CD8⁺ T cells as the main pathologic drivers of polymyositis. Furthermore, the transcriptome analysis of muscle tissue from hPBMC mice reveal extensive upregulation of characteristic genes of polymyositis, providing further support that hPBMC mice accurately reflect the pathophysiology of myositis in humans. Finally, administration of prednisolone or tacrolimus, which are commonly used for IIM treatment, leads to significant alleviation of myositis findings. Therefore, we propose that hPBMC mice should be considered as a model that accurately reflects the pathophysiology of myositis in human patients.

Vascular smooth muscle cells (VSMCs) and endothelial cells (ECs) act together to regulate blood pressure and systemic blood flow by appropriately adjusting blood vessel diameter in response to biochemical or biomechanical stimuli. Ion channels that are expressed in these cells regulate membrane potential and cytosolic Ca²⁺ concentration ([Ca²⁺]_cyt) in response to such stimuli. The subsets of these ion channels involved in Ca²⁺ signaling often form molecular complexes with intracellular molecules via scaffolding proteins. This allows Ca²⁺ signaling to be tightly controlled in localized areas within the cell, resulting in a balanced vascular tone. When hypertensive stimuli are applied to blood vessels for extended periods, gene expression in these vascular cells can change dramatically. For example, alteration in ion channel expression often induces electrical remodeling that produces a depolarization of the membrane potential and elevated [Ca²⁺]_cyt. Coupled with endothelial dysfunction blood vessels undergo functional remodeling characterized by enhanced vasoconstriction. In addition, pathological challenges to vascular cells can induce inflammatory gene products that may promote leukocyte infiltration, in part through Ca²⁺-dependent pathways. Macrophages accumulating in the vascular adventitia promote fibrosis through extracellular matrix turnover, and cause structural remodeling of blood vessels. This functional and structural remodeling often leads to chronic hypertension affecting not only blood vessels, but also multiple organs including the brain, kidneys, and heart, thus increasing the risk of severe cardiovascular events. In this review, we outline recent advances in multidisciplinary research concerning Ca²⁺ signaling in VSMCs and ECs, with an emphasis on the mechanisms underlying functional and structural vascular remodeling.

Cell-cell fusion is a vital biological process where the membranes of two or more cells merge to form a syncytium. This phenomenon is critical in various physiological and pathological contexts, including embryonic development, tissue repair, immune responses, and the progression of several diseases. Osteoclasts, which are cells from the monocyte/macrophage lineage responsible for bone resorption, have enhanced functionality due to cell fusion. Additionally, other multinucleated giant cells (MGCs) also arise from the fusion of monocytes and macrophages, typically during chronic inflammation and reactions to foreign materials such as prostheses or medical devices. Foreign body giant cells (FBGCs) and Langhans giant cells (LGCs) emerge only under pathological conditions and are involved in phagocytosis, antigen presentation, and the secretion of inflammatory mediators. This review provides a comprehensive overview of the mechanisms underlying the formation of multinucleated cells, with a particular emphasis on macrophages and osteoclasts. Elucidating the intracellular structures, signaling cascades, and fusion-mediating proteins involved in cell-cell fusion enhances our understanding of this fundamental biological process and helps identify potential therapeutic targets for disorders mediated by cell fusion.

Background: Macrophages and mesenchymal stem cells (MSCs) engage in crucial interplay during inflammation and have significant roles in tissue regeneration. Synovial MSCs, as key players in joint regeneration, are known to proliferate together with macrophages in synovitis. However, the crosstalk between synovial MSCs and macrophages remains unclear. In this study, we investigated changes in the activation of synovial MSCs in inflamed rat knees following selective depletion of macrophages with clodronate liposomes.

Methods: Acute inflammation was induced in rat knee joints by injection of carrageenan (day 0). Clodronate liposomes were administered intra-articularly on days 1 and 4 to deplete macrophages, with empty liposomes as a control. Knee joints were collected on day 7 for evaluation by histology, flow cytometry, and colony-forming assays. Concurrently, synovial MSCs were cultured and subjected to proliferation assays, flow cytometry, and chondrogenesis assessments. We also analyzed their crosstalk using single-cell RNA sequencing (scRNA-seq).

Results: Clodronate liposome treatment significantly reduced CD68-positive macrophage numbers and suppressed synovitis. Immunohistochemistry and flow cytometry showed decreased expression of CD68 (a macrophage marker) and CD44 and CD271 (MSC markers) in the clodronate group, while CD73 expression remained unchanged. The number of colony-forming cells per 1000 nucleated cells and per gram of synovium was significantly lower in the clodronate group than in the control group. Cultured synovial MSCs from both groups showed comparable proliferation, surface antigen expression, and chondrogenic capacity. scRNA-seq identified seven distinct synovial fibroblast (SF) subsets, with a notable decrease in the Mki67⁺ SF subset, corresponding to synovial MSCs, in the clodronate group. Clodronate treatment downregulated genes related to extracellular matrix organization and anabolic pathways in Mki67⁺ SF. Cell-cell communication analysis revealed diminished Nampt and Spp1 signaling interaction between macrophages and Mki67⁺ SF and diminished Ccl7, Spp1, and Csf1 signaling interaction between Mki67⁺ SF and macrophages in the clodronate group. Spp1 and Nampt promoted the proliferation and/or chondrogenesis of synovial MSCs.

Conclusions: Macrophage depletion with clodronate liposomes suppressed synovitis and reduced the number and activity of synovial MSCs, highlighting the significance of macrophage-derived Nampt and Spp1 signals in synovial MSC activation. These findings offer potential therapeutic strategies to promote joint tissue regeneration by enhancing beneficial signals between macrophages and synovial MSCs.