Inflammation and Regeneration最新文献

The molecular platforms of the innate immune system are essential to recognize pathologic external factors that are crucial to differentiate these danger signals from host motifs. A set of sensors recognizing pathologic factors is present and defined as a membrane-bound family of Toll-like receptors as well as the cytosolic ones including the family of nucleotide-binding domain leucine-rich repeat proteins. In this regard, the inflammasomes have been identified as an innate immune sensor toward pathologic external factors as well as endogenous damage-associated molecular pattern signals transducing from the above-mentioned receptors to gene expressions. Recent research has shown novel findings in inflammasome biology and genetics which lead to the alteration of diagnosis and management in autoinflammatory diseases as well as developing novel treatments, including the examples of nucleotide-binding domain leucine-rich repeat proteins-inflammasomes and pyrin-inflammasomes. The pyrin protein is encoded by the Mediterranean Fever gene on chromosome 16 that acts as a major regulatory component of the inflammasome, and is responsible for familial Mediterranean fever. We have recently examined the whole nucleotide sequence of the Mediterranean Fever gene in Japanese familial Mediterranean fever patients and revealed single nucleotide variants associated with the susceptibility of familial Mediterranean fever from a nation-wide survey by the next-generation sequencing. In a cytokine profile analysis of familial Mediterranean fever patients, we have found that interleukin-6 is considered to be one of the most crucial cytokines in familial Mediterranean fever attack since interleukin-6 had the best performance for distinguishing familial Mediterranean fever in attack from healthy controls or familial Mediterranean fever in remission, and in vitro interleukin-6 production is regulated by microRNAs-204-3p/phosphoinositide 3-kinase g pathway. Accordingly, we have been investigating the efficacy and safety of anti-human interleukin-6 receptor monoclonal antibody, tocilizumab, in patients with familial Mediterranean fever refractory or intolerant to colchicine through an investigator-initiated clinical trial supported by the Japan Agency for Medical Research and Development. Like interleukin-1b, interleukin-18 can be processed by caspase-1 and proteinase-3 to be activated within the inflammasomes. We have also found the importance of interleukin-18 in several autoinflammatory conditions. Recently, the concept of autoinflammation is widely distributed into many common diseases; thus, the attention to a wide spectrum of diseases MEFV gene deeply involved is required.

Recent advances in our understanding in the immune-mediated inflammatory diseases (IMID) are explored and promoted by the targeted treatment. Among these targets, cytokines and cytokine receptors have become the good candidates for the drug development. In this review, the cytokine and cytokine receptors, which are approved in IMID, are overviewed, and modalities of the treatment, the role of cytokines and cytokine receptors in each disease, and the updated molecular information by modern technologies in rheumatoid arthritis as a role model are shown and discussed for the future perspectives.

Background: Brachial plexus avulsion (BPA) physically involves the detachment of spinal nerve roots themselves and the associated spinal cord segment, leading to permanent paralysis of motor function of the upper limb. Root avulsion induces severe pathological changes, including inflammatory reaction, oxidative damage, and finally massive motoneuron apoptosis. Quercetin (QCN), a polyphenolic flavonoid found in abundance in fruit and vegetables, has been reported to possess anti-oxidative, anti-inflammatory, and neuroprotective effects in many experimental models of both central nervous system (CNS) and peripheral nervous system (PNS) disorders. The purpose of this study was to investigate whether QCN could improve motor function recovery after C5-7 ventral root avulsion and C6 reimplantation in a rat model of BPA.

Methods: The right fifth cervical (C5) to C7 ventral roots were avulsed followed by re-implantation of only C6 to establish the spinal root avulsion plus re-implantation model in rats. After surgery, rats were treated with QCN (25, 50, and 100 mg/kg) by gavage for 2 or 8 consecutive weeks. The effects of QCN were assessed using behavior test (Terzis grooming test, TGT) and histological evaluation. The molecular mechanisms were determined by immunohistochemistry analysis and western blotting.

Results: Our results demonstrated that QCN significantly expedited motor function recovery in the forelimb as shown by the increased Terzis grooming test score, and accelerated motor axon regeneration as evidenced by the ascending number of Fluoro-Ruby-labeled and P75-positive regenerative motoneurons. The raised ChAT-immunopositive and cresyl violet-stained neurons indicated the enhanced survival of motoneurons by QCN administration. Furthermore, QCN treatment markedly alleviated muscle atrophy, restored functional motor endplates in biceps and inhibited the microglial and astroglia activation via modulating Nrf2/HO-1 and neurotrophin/Akt/MAPK signaling pathway.

Conclusions: Taken together, these findings have for the first time unequivocally indicated that QCN has promising potential for further development into a novel therapeutic in conjunction with reimplantation surgery for the treatment of BPA. .

Background: Type 1 diabetes (T1D) is a T-cell-mediated autoimmune disease characterized by the irreversible destruction of insulin-producing β-cells in pancreatic islets. Helper and cytotoxic T-cells and cytokine production, which is impaired by this process, take a synergetic role in β-cell destruction, and hyperglycemia develops due to insulin deficiency in the body. Mesenchymal stem cells (MSCs) appear like an excellent therapeutic tool for autoimmune diseases with pluripotent, regenerative, and immunosuppressive properties. Paracrine factors released from MSCs play a role in immunomodulation by increasing angiogenesis and proliferation and suppressing apoptosis. In this context, the study aims to investigate the therapeutic effects of MSC's secretomes by conditioned medium (CM) obtained from human umbilical cord-derived MSCs cultured in 2-dimensional (2D) and 3-dimensional (3D) environments in the T1D model.

Methods: First, MSCs were isolated from the human umbilical cord, and the cells were characterized. Then, two different CMs were prepared by culturing MSCs in 2D and 3D environments. The CM contents were analyzed in terms of total protein, IL-4, IL-10, IL-17, and IFN-λ. In vivo studies were performed in Sprague-Dawley-type rats with an autoimmune T1D model, and twelve doses of CM were administered intraperitoneally for 4 weeks within the framework of a particular treatment model. In order to evaluate immunomodulation, the Treg population was determined in lymphocytes isolated from the spleen after sacrification, and IL-4, IL-10, IL-17, and IFN-λ cytokines were analyzed in serum. Finally, β-cell regeneration was evaluated immunohistochemically by labeling Pdx1, Nkx6.1, and insulin markers, which are critical for the formation of β-cells.

Results: Total protein and IL-4 levels were higher in 3D-CM compared to 2D-CM. In vivo results showed that CMs induce the Treg population and regulate cytokine release. When the immunohistochemical results were evaluated together, it was determined that CM application significantly increased the rate of β-cells in the islets. This increase was at the highest level in the 3D-CM applied group.

Conclusion: The dual therapeutic effect of MSC-CM on immunomodulation and homeostasis/regeneration of β-cells in the T1D model has been demonstrated. Furthermore, this effect could be improved by using 3D scaffolds for culturing MSCs while preparing CM.

For all living organisms, the adaptation to outside environments is an essential determinant to survive natural and artificial selections and to sustain the whole ecosystem intact with functional biodiversity. Likewise, cancer cells have similar characteristics that evade not only stresses from the host-internal innate and adaptive immune systems but also those from host-externally administered therapeutic interventions. Such selfish characteristics of cancer cells lead to the formation of cancerous ecosystem with a wide variety of phenotypic heterogeneity, which should be called cancer "egosystem" from the host point of view. Recently increasing evidence demonstrates that cancer stem cells (CSCs) are responsible for this cancer egosystem by effectively exploiting host inflammatory and hematopoietic cells and thereby reconstructing their own advantageous niches, which may well be a driving force in cancer recurrence. CSCs are further likely to render multiple niches mutually interconnected and cooperating as a network to support back CSCs themselves. Here, we summarize a recently identified iron-replenishing niche network self-organized by glioma CSCs (GSCs) through remote regulation of host myeloid and erythroid lineage cells. GSCs recruit bone marrow (BM)-derived inflammatory monocytes into tumor parenchyma, facilitate their differentiation into macrophages (Mφs) and skew their polarization into pro-tumoral phenotype, i.e., tumor-associated Mφs (TAMs). Meanwhile, GSCs distantly enhance erythropoiesis in host hematopoietic organs like BM and spleen potentially by secreting some soluble mediators that maintain continuous supply of erythrocytes within tumors. In addition, as normal red pulp Mφs (RPMs) under steady state conditions in spleen recycle iron by phagocytosing the aged or damaged erythrocytes (a/dECs) and release it in time of need, TAMs at least in gliomas phagocytose the hemorrhaged erythrocytes within tumors and potentially serve as a source of iron, an important nutrient indispensable to GSC survival and glioma progression. Taken together, these studies provide the substantial evidence that CSCs have a unique strategy to orchestrate multiple niches as an ecosystem that threatens the host living, which in this sense must be an egosystem. Targeting such an adaptive subpopulation of CSCs could achieve drastic disturbance of the CSC niches and subsequent extinction of malignant neoplasms.

Background: The coronavirus disease 2019 (COVID-19) pandemic is widespread; however, accurate predictors of refractory cases have not yet been established. Circulating extracellular vesicles, involved in many pathological processes, are ideal resources for biomarker exploration.

Methods: To identify potential serum biomarkers and examine the proteins associated with the pathogenesis of refractory COVID-19, we conducted high-coverage proteomics on serum extracellular vesicles collected from 12 patients with COVID-19 at different disease severity levels and 4 healthy controls. Furthermore, single-cell RNA sequencing of peripheral blood mononuclear cells collected from 10 patients with COVID-19 and 5 healthy controls was performed.

Results: Among the 3046 extracellular vesicle proteins that were identified, expression of MACROH2A1 was significantly elevated in refractory cases compared to non-refractory cases; moreover, its expression was increased according to disease severity. In single-cell RNA sequencing of peripheral blood mononuclear cells, the expression of MACROH2A1 was localized to monocytes and elevated in critical cases. Consistently, single-nucleus RNA sequencing of lung tissues revealed that MACROH2A1 was highly expressed in monocytes and macrophages and was significantly elevated in fatal COVID-19. Moreover, molecular network analysis showed that pathways such as "estrogen signaling pathway," "p160 steroid receptor coactivator (SRC) signaling pathway," and "transcriptional regulation by STAT" were enriched in the transcriptome of monocytes in the peripheral blood mononuclear cells and lungs, and they were also commonly enriched in extracellular vesicle proteomics.

Conclusions: Our findings highlight that MACROH2A1 in extracellular vesicles is a potential biomarker of refractory COVID-19 and may reflect the pathogenesis of COVID-19 in monocytes.

As an important part of adaptive immunity, T cells are indispensable in the defense against pathogens including viruses. SARS-CoV-2 is a new human coronavirus that occurred at the end of 2019 and has caused the COVID-19 pandemic. Nevertheless, most of the infected patients recovered without any antiviral therapies, suggesting an effective immunity developed in the bodies. T cell immunity responds upon SARS-CoV-2 infection or vaccination and plays crucial roles in eliminating the viruses and generating T cell memory. Specifically, a subpopulation of CD4⁺ T cells could support the production of anti-SARS-CoV-2 antibodies, and cytotoxic CD8⁺ T cells are also protective against the infection. SARS-CoV-2-recognizing T cells could be detected in SARS-CoV-2-unexposed donors, but the role of these cross-reactive T cells is still in debate. T cell responses could be diverse across individuals, mainly due to the polymorphism of HLAs. Thus, compared to antibodies, T cell responses are generally less affected by the mutations of SARS-CoV-2 variants. Up to now, a huge number of studies on SARS-CoV-2-responsive T cells have been published. In this review, we introduced some major findings addressing the questions in the main aspects about T cell responses elicited by SARS-CoV-2, to summarize the current understanding of COVID-19.

Background: Different factors may lead to hepatitis. Among which are liver inflammation and poisoning. We chose two hepatitis models, typical for these two underlying causes. Thus, we aimed to characterize the role of protease-activated receptor 2 (Par2) in liver regeneration and inflammation to reconcile Par2 conflicting role in many damage models, which sometimes aggravates the induced damage and sometimes alleviates it.

Methods: WT and knockout (Par2KO) mice were injected with concanavalin A (ConA) to induce immune-mediated hepatitis or with carbon tetrachloride (CCl₄) to elicit direct hepatic damage. To distinguish the immune component from the liver regenerative response, we conducted bone marrow (BM) replacements of WT and Par2KO mice and repeated the damage models.

Results: ConA injection caused limited damage in Par2KO mice livers, while in the WT mice severe damage followed by leukocyte infiltration was evident. Reciprocal BM replacement of WT and Par2KO showed that WT BM-reconstituted Par2KO mice displayed marked liver damage, while in Par2KO BM-reconstituted WT mice, the tissue was generally protected. In the CCl₄ direct damage model, hepatocytes regenerated in WT mice, whereas Par2KO mice failed to recover. Reciprocal BM replacement did not show significant differences in hepatic regeneration. In Par2KO mice, hepatitis was more apparent, while WT recovered regardless of the BM origin.

Conclusions: We conclude that Par2 activation in the immune system aggravates hepatitis and that Par2 activation in the damaged tissue promotes liver regeneration. When we incorporate this finding and revisit the literature reports, we reconciled the conflicts surrounding Par2's role in injury, recovery, and inflammation.

Coronaviruses regularly cause outbreaks of zoonotic diseases characterized by severe pneumonia. The new coronavirus, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has caused the global pandemic disease COVID-19 that began at the end of 2019 and spread rapidly owing to its infectious nature and rapidly progressing pneumonia. Although the infectivity of SARS-CoV-2 is high, indicated by the worldwide spread of the disease in a very short period, many individuals displayed only subclinical infection, and some of them transmitted the disease to individuals who then developed a severe symptomatic infection. Furthermore, there are differences in the severity of infection across countries, which can be attributed to factors such as the emergence of viral mutations in a short period of time as well as to the immune responses to viral factors. Anti-viral immunity generally consists of neutralizing antibodies that block viral infection and cytotoxic CD8⁺ T cells that eliminate the virus-infected cells. There is compelling evidence for the role of neutralizing antibodies in protective immunity in SARS-CoV-2 infection. However, the role of CD4⁺ and CD8⁺ T cells after the viral entry is complex and warrants a comprehensive discussion. Here, we discuss the protection afforded by cellular immunity against initial infection and development of severe disease. The initial failure of cellular immunity to control the infection worsens the clinical outcomes and functional profiles that inflict tissue damage without effectively eliminating viral reservoirs, while robust T cell responses are associated with mild outcomes. We also discuss persistent long-lasting memory T cell-mediated protection after infection or vaccination, which is rather complicated as it may involve SARS-CoV-2-specific cytotoxic T lymphocytes or cross-reactivity with previously infected seasonal coronaviruses, which are largely related to HLA genotypes. In addition, cross-reactivity with mutant strains is also discussed. Lastly, we discuss appropriate measures to be taken against the disease for immunocompromised patients. In conclusion, we provide evidence and discuss the causal relationship between natural infection- or vaccine-mediated memory T cell immunity and severity of COVID-19. This review is expected to provide a basis to develop strategies for the next generation of T cell-focused vaccines and aid in ending the current pandemic.

Background: The emerging concepts of fetal-like reprogramming following tissue injury have been well recognized as an important cue for resolving regenerative mechanisms of intestinal epithelium during inflammation. We previously revealed that the remodeling of mesenchyme with collagen fibril induces YAP/TAZ-dependent fate conversion of intestinal/colonic epithelial cells covering the wound bed towards fetal-like progenitors. To fully elucidate the mechanisms underlying the link between extracellular matrix (ECM) remodeling of mesenchyme and fetal-like reprogramming of epithelial cells, it is critical to understand how collagen type I influence the phenotype of epithelial cells. In this study, we utilize collagen sphere, which is the epithelial organoids cultured in purified collagen type I, to understand the mechanisms of the inflammatory associated reprogramming. Resolving the entire landscape of regulatory networks of the collagen sphere is useful to dissect the reprogrammed signature of the intestinal epithelium.

Methods: We performed microarray, RNA-seq, and ATAC-seq analyses of the murine collagen sphere in comparison with Matrigel organoid and fetal enterosphere (FEnS). We subsequently cultured human colon epithelium in collagen type I and performed RNA-seq analysis. The enriched genes were validated by gene expression comparison between published gene sets and immunofluorescence in pathological specimens of ulcerative colitis (UC).

Results: The murine collagen sphere was confirmed to have inflammatory and regenerative signatures from RNA-seq analysis. ATAC-seq analysis confirmed that the YAP/TAZ-TEAD axis plays a central role in the induction of the distinctive signature. Among them, TAZ has implied its relevant role in the process of reprogramming and the ATAC-based motif analysis demonstrated not only Tead proteins, but also Fra1 and Runx2, which are highly enriched in the collagen sphere. Additionally, the human collagen sphere also showed a highly significant enrichment of both inflammatory and fetal-like signatures. Immunofluorescence staining confirmed that the representative genes in the human collagen sphere were highly expressed in the inflammatory region of ulcerative colitis.

Conclusions: Collagen type I showed a significant influence in the acquisition of the reprogrammed inflammatory signature in both mice and humans. Dissection of the cell fate conversion and its mechanisms shown in this study can enhance our understanding of how the epithelial signature of inflammation is influenced by the ECM niche.