{"title":"Regeneration of invariant natural killer T (iNKT) cells: application of iPSC technology for iNKT cell-targeted tumor immunotherapy.","authors":"Takahiro Aoki, Shinichiro Motohashi, Haruhiko Koseki","doi":"10.1186/s41232-023-00275-5","DOIUrl":"https://doi.org/10.1186/s41232-023-00275-5","url":null,"abstract":"<p><p>Invariant natural killer T (iNKT) cells are a subset of innate-like T cells restricted by a major histocompatibility complex (MHC) class I-like molecule, CD1d. iNKT cells express an invariant T cell receptor (TCR) encoded by Vα14 Jα18 in mice and Vα24 Jα18 in humans and are activated by recognizing glycolipid antigens, such as α-galactosylceramide (αGalCer), presented by CD1d. iNKT cells exhibit anti-tumor activity via their NK-like cytotoxicity and adjuvant activity. Although iNKT cell-targeted immunotherapy is a conceptually promising approach, we still found a technical hurdle for its clinical implementation which is mainly due to the low frequency of iNKT cells, particularly in humans. To compensate for this, we proposed to generate adequate numbers of clinically competent NKT cells from induced pluripotent stem cells (iPSCs) for cancer immunotherapy. Toward this goal, we first obtained the proof of concept (POC) for this approach in mice. We developed a technology to differentiate iPSCs into iNKT cells (iPSC-iNKT cells) and found iPSC-iNKT cells efficiently rejected a syngeneic experimental thymoma by inducing antigen-specific CD8 T cells. After achieving the POC in mice, we developed human iPSC-iNKT cells, which had a high correlation in their gene expression profiles with parental iNKT cells. Human iPSC-iNKT cells also exhibited anti-tumor activity and adjuvant activity for human NK cells in vivo. Based on this supporting evidence for the anti-tumor activity of human iPSC-iNKT cells, we began to generate good manufacturing practice (GMP)-grade iPSC-iNKT cells. As of now, the first-in-human clinical trial of iPSC-iNKT cell therapy is ongoing as a single-agent, dose-escalation study for patients with advanced head and neck cancer. Demonstration of the safety of iPSC-iNKT cell therapy may allow us to improve the strategy by further reinforcing the therapeutic activity of iPSC-iNKT, cells either by gene-editing or combinatorial use with other immune cell products such as dendritic cells. Sixteen years after the establishment of the iPSC technology, we are reaching the first checkpoint to evaluate the clinical efficacy of iPSC-derived immune cells.</p>","PeriodicalId":13588,"journal":{"name":"Inflammation and Regeneration","volume":"43 1","pages":"27"},"PeriodicalIF":8.1,"publicationDate":"2023-05-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10176773/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9459732","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Neuroinflammation in Alzheimer's disease: microglial signature and their relevance to disease.","authors":"Akira Sobue, Okiru Komine, Koji Yamanaka","doi":"10.1186/s41232-023-00277-3","DOIUrl":"https://doi.org/10.1186/s41232-023-00277-3","url":null,"abstract":"<p><p>Alzheimer's disease (AD) is the most common form of dementia, pathologically characterized by senile plaques and neurofibrillary tangles (NFTs), resulting in neurodegeneration. Neuroinflammation, defined as the activation of glial cells such as microglia and astrocytes, is observed surrounding senile plaques and affected neurons in AD. Recently conducted genome-wide association studies (GWAS) indicate that a large section of identified AD risk genes are involved in immune responses and are enriched in microglia. Microglia are innate immune cells in the central nervous system (CNS), which are involved in immune surveillance and maintenance of homeostasis in the CNS. Recently, a novel subpopulation of activated microglia named as disease-associated microglia (DAM), also known as activated response microglia (ARM) or microglial neurodegenerative phenotype (MGnD), was identified in AD model mice. These microglia closely associate with β-amyloid (Aβ) plaques and exhibit characteristic gene expression profiles accompanied with reduced expressions of homeostatic microglial genes. However, it remains unclear whether decreased homeostatic microglia functions or increased DAM/ARM/MGnD functions correlate with the degree of neuronal loss in AD. To translate the results of rodent studies to human AD, precuneus, the brain region vulnerable to β-amyloid accumulation in preclinical AD, is of high interest, as it can provide novel insights into the mechanisms of microglia response to Aβ in early AD. In this study, we performed comparative analyses of gene expression profiles of microglia among three representative neurodegenerative mouse models and the human precunei with early AD pathology. We proceeded to evaluate the identified genes as potential therapeutic targets for AD. We believe that our findings will provide important resources to better understand the role of glial dysfunction in AD.</p>","PeriodicalId":13588,"journal":{"name":"Inflammation and Regeneration","volume":"43 1","pages":"26"},"PeriodicalIF":8.1,"publicationDate":"2023-05-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10170691/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9505630","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Nicole Labusek, Yanis Mouloud, Christian Köster, Eva Diesterbeck, Tobias Tertel, Constanze Wiek, Helmut Hanenberg, Peter A Horn, Ursula Felderhoff-Müser, Ivo Bendix, Bernd Giebel, Josephine Herz
{"title":"Extracellular vesicles from immortalized mesenchymal stromal cells protect against neonatal hypoxic-ischemic brain injury.","authors":"Nicole Labusek, Yanis Mouloud, Christian Köster, Eva Diesterbeck, Tobias Tertel, Constanze Wiek, Helmut Hanenberg, Peter A Horn, Ursula Felderhoff-Müser, Ivo Bendix, Bernd Giebel, Josephine Herz","doi":"10.1186/s41232-023-00274-6","DOIUrl":"https://doi.org/10.1186/s41232-023-00274-6","url":null,"abstract":"<p><strong>Background: </strong>Human mesenchymal stromal cell (MSC)-derived extracellular vesicles (EV) revealed neuroprotective potentials in various brain injury models, including neonatal encephalopathy caused by hypoxia-ischemia (HI). However, for clinical translation of an MSC-EV therapy, scaled manufacturing strategies are required, which is challenging with primary MSCs due to inter- and intra-donor heterogeneities. Therefore, we established a clonally expanded and immortalized human MSC line (ciMSC) and compared the neuroprotective potential of their EVs with EVs from primary MSCs in a murine model of HI-induced brain injury. In vivo activities of ciMSC-EVs were comprehensively characterized according to their proposed multimodal mechanisms of action.</p><p><strong>Methods: </strong>Nine-day-old C57BL/6 mice were exposed to HI followed by repetitive intranasal delivery of primary MSC-EVs or ciMSC-EVs 1, 3, and 5 days after HI. Sham-operated animals served as healthy controls. To compare neuroprotective effects of both EV preparations, total and regional brain atrophy was assessed by cresyl-violet-staining 7 days after HI. Immunohistochemistry, western blot, and real-time PCR were performed to investigate neuroinflammatory and regenerative processes. The amount of peripheral inflammatory mediators was evaluated by multiplex analyses in serum samples.</p><p><strong>Results: </strong>Intranasal delivery of ciMSC-EVs and primary MSC-EVs comparably protected neonatal mice from HI-induced brain tissue atrophy. Mechanistically, ciMSC-EV application reduced microglia activation and astrogliosis, endothelial activation, and leukocyte infiltration. These effects were associated with a downregulation of the pro-inflammatory cytokine IL-1 beta and an elevated expression of the anti-inflammatory cytokines IL-4 and TGF-beta in the brain, while concentrations of cytokines in the peripheral blood were not affected. ciMSC-EV-mediated anti-inflammatory effects in the brain were accompanied by an increased neural progenitor and endothelial cell proliferation, oligodendrocyte maturation, and neurotrophic growth factor expression.</p><p><strong>Conclusion: </strong>Our data demonstrate that ciMSC-EVs conserve neuroprotective effects of primary MSC-EVs via inhibition of neuroinflammation and promotion of neuroregeneration. Since ciMSCs can overcome challenges associated with MSC heterogeneity, they appear as an ideal cell source for the scaled manufacturing of EV-based therapeutics to treat neonatal and possibly also adult brain injury.</p>","PeriodicalId":13588,"journal":{"name":"Inflammation and Regeneration","volume":"43 1","pages":"24"},"PeriodicalIF":8.1,"publicationDate":"2023-04-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10108458/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9678980","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"A human induced pluripotent stem cell model from a patient with hereditary cerebral small vessel disease carrying a heterozygous R302Q mutation in HTRA1.","authors":"Emi Qian, Masahiro Uemura, Hiroya Kobayashi, Shiho Nakamura, Fumiko Ozawa, Sho Yoshimatsu, Mitsuru Ishikawa, Osamu Onodera, Satoru Morimoto, Hideyuki Okano","doi":"10.1186/s41232-023-00273-7","DOIUrl":"https://doi.org/10.1186/s41232-023-00273-7","url":null,"abstract":"<p><p>Cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy (CARASIL) is an inherited cerebral small vessel disease (CSVD) caused by biallelic mutations in the high-temperature requirement serine peptidase A1 (HTRA1) gene. Even heterozygous mutations in HTRA1 are recently revealed to cause cardinal clinical features of CSVD. Here, we report the first establishment of a human induced pluripotent stem cell (hiPSC) line from a patient with heterozygous HTRA1-related CSVD. Peripheral blood mononuclear cells (PBMCs) were reprogrammed by the transfection of episomal vectors encoding human OCT3/4 (POU5F1), SOX2, KLF4, L-MYC, LIN28, and a murine dominant-negative mutant of p53 (mp53DD). The established iPSCs had normal morphology as human pluripotent stem cells and normal karyotype (46XX). Moreover, we found that the HTRA1 missense mutation (c.905G>A, p.R302Q) was heterozygous. These iPSCs expressed pluripotency-related markers and had the potential to differentiate into all three germ layers in vitro. HTRA1 and the supposed disease-associated gene NOG were differentially expressed in the patient iPSCs at mRNA levels compared to those of control lines. The iPSC line would facilitate in vitro research for understanding the cellular pathomechanisms caused by the HTRA1 mutation including its dominant-negative effect.</p>","PeriodicalId":13588,"journal":{"name":"Inflammation and Regeneration","volume":"43 1","pages":"23"},"PeriodicalIF":8.1,"publicationDate":"2023-04-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10069112/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9253166","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Molecular hydrogen promotes wound healing by inducing early epidermal stem cell proliferation and extracellular matrix deposition.","authors":"Pengxiang Zhao, Zheng Dang, Mengyu Liu, Dazhi Guo, Ruiliu Luo, Mingzi Zhang, Fei Xie, Xujuan Zhang, Youbin Wang, Shuyi Pan, Xuemei Ma","doi":"10.1186/s41232-023-00271-9","DOIUrl":"https://doi.org/10.1186/s41232-023-00271-9","url":null,"abstract":"<p><strong>Background: </strong>Despite progress in developing wound care strategies, there is currently no treatment that promotes the self-tissue repair capabilities. H<sub>2</sub> has been shown to effectively protect cells and tissues from oxidative and inflammatory damage. While comprehensive effects and how H<sub>2</sub> functions in wound healing remains unknown, especially for the link between H<sub>2</sub> and extracellular matrix (ECM) deposition and epidermal stem cells (EpSCs) activation.</p><p><strong>Methods: </strong>Here, we established a cutaneous aseptic wound model and applied a high concentration of H<sub>2</sub> (66% H<sub>2</sub>) in a treatment chamber. Molecular mechanisms and the effects of healing were evaluated by gene functional enrichment analysis, digital spatial profiler analysis, blood perfusion/oxygen detection assay, in vitro tube formation assay, enzyme-linked immunosorbent assay, immunofluorescent staining, non-targeted metabonomic analysis, flow cytometry, transmission electron microscope, and live-cell imaging.</p><p><strong>Results: </strong>We revealed that a high concentration of H<sub>2</sub> (66% H<sub>2</sub>) greatly increased the healing rate (3 times higher than the control group) on day 11 post-wounding. The effect was not dependent on O<sub>2</sub> or anti-reactive oxygen species functions. Histological and cellular experiments proved the fast re-epithelialization in the H<sub>2</sub> group. ECM components early (3 days post-wounding) deposition were found in the H<sub>2</sub> group of the proximal wound, especially for the dermal col-I, epidermal col-III, and dermis-epidermis-junction col-XVII. H<sub>2</sub> accelerated early autologous EpSCs proliferation (1-2 days in advance) and then differentiation into myoepithelial cells. These epidermal myoepithelial cells could further contribute to ECM deposition. Other beneficial outcomes include sustained moist healing, greater vascularization, less T-helper-1 and T-helper-17 cell-related systemic inflammation, and better tissue remodelling.</p><p><strong>Conclusion: </strong>We have discovered a novel pattern of wound healing induced by molecular hydrogen treatment. This is the first time to reveal the direct link between H<sub>2</sub> and ECM deposition and EpSCs activation. These H<sub>2</sub>-induced multiple advantages in healing may be related to the enhancement of cell viability in various cells and the maintenance of mitochondrial functions at a basic level in the biological processes of life.</p>","PeriodicalId":13588,"journal":{"name":"Inflammation and Regeneration","volume":"43 1","pages":"22"},"PeriodicalIF":8.1,"publicationDate":"2023-03-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10044764/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9572174","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Group 2 innate lymphoid cells and their surrounding environment.","authors":"Maiko Naito, Atsushi Kumanogoh","doi":"10.1186/s41232-023-00272-8","DOIUrl":"https://doi.org/10.1186/s41232-023-00272-8","url":null,"abstract":"<p><p>Since the discovery of group 2 innate lymphoid cells (ILC2s) in 2010, subsequent studies have revealed their developmental pathways, mechanisms of activation and regulation, and immunological roles in tissue homeostasis and tissue-specific diseases in various organs. Although ILC2s are known to express tissue-specific features depending on where they reside, how the surrounding environment affects the functions of ILC2s remains to be fully elucidated. Recent histologic analyses revealed that ILC2s resides in specific perivascular regions in peripheral tissues with their function being controlled by the surrounding cells via cytokines, lipid mediators, neurotransmitters, and cell-cell interactions through surface molecules. This review summarizes the interactions between ILC2s and surrounding cells, including epithelial cells, neurons, immune cells, and mesenchymal cells, with the objective of promoting the development of novel diagnostic and therapeutic methods for ILC2-related diseases.</p>","PeriodicalId":13588,"journal":{"name":"Inflammation and Regeneration","volume":"43 1","pages":"21"},"PeriodicalIF":8.1,"publicationDate":"2023-03-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10026507/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9214613","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Ryusei Kaneko, Ako Matsui, Mahiro Watanabe, Yoshihiro Harada, Mitsuhiro Kanamori, Natsumi Awata, Mio Kawazoe, Tomoaki Takao, Yutaro Kobayashi, Chie Kikutake, Mikita Suyama, Takashi Saito, Takaomi C Saido, Minako Ito
{"title":"Increased neutrophils in inflammatory bowel disease accelerate the accumulation of amyloid plaques in the mouse model of Alzheimer's disease.","authors":"Ryusei Kaneko, Ako Matsui, Mahiro Watanabe, Yoshihiro Harada, Mitsuhiro Kanamori, Natsumi Awata, Mio Kawazoe, Tomoaki Takao, Yutaro Kobayashi, Chie Kikutake, Mikita Suyama, Takashi Saito, Takaomi C Saido, Minako Ito","doi":"10.1186/s41232-023-00257-7","DOIUrl":"https://doi.org/10.1186/s41232-023-00257-7","url":null,"abstract":"<p><strong>Background: </strong>Alzheimer's disease (AD) is one of the neurodegenerative diseases and characterized by the appearance and accumulation of amyloid-β (Aβ) aggregates and phosphorylated tau with aging. The aggregation of Aβ, which is the main component of senile plaques, is closely associated with disease progression. App<sup>NL-G-F</sup> mice, a mouse model of AD, have three familial AD mutations in the amyloid-β precursor gene and exhibit age-dependent AD-like symptoms and pathology. Gut-brain interactions have attracted considerable attention and inflammatory bowel disease (IBD) has been associated with a higher risk of dementia, especially AD, in humans. However, the underlying mechanisms and the effects of intestinal inflammation on the brain in AD remain largely unknown. Therefore, we aimed to investigate the effects of intestinal inflammation on AD pathogenesis.</p><p><strong>Methods: </strong>Wild-type and App<sup>NL-G-F</sup> mice at three months of age were fed with water containing 2% dextran sulfate sodium (DSS) to induce colitis. Immune cells in the brain were analyzed using single-cell RNA sequencing (scRNA-seq) analysis, and the aggregation of Aβ protein in the brain was analyzed via immunohistochemistry.</p><p><strong>Results: </strong>An increase in aggregated Aβ was observed in the brains of App<sup>NL-G-F</sup> mice with acute intestinal inflammation. Detailed scRNA-seq analysis of immune cells in the brain showed that neutrophils in the brain increased after acute enteritis. Eliminating neutrophils by antibodies suppressed the accumulation of Aβ, which increased because of intestinal inflammation.</p><p><strong>Conclusion: </strong>These results suggest that neutrophils infiltrate the AD brain parenchyma when acute colitis occurs, and this infiltration is significantly related to disease progression. Therefore, we propose that neutrophil-targeted therapies could reduce Aβ accumulation observed in early AD and prevent the increased risk of AD due to colitis.</p>","PeriodicalId":13588,"journal":{"name":"Inflammation and Regeneration","volume":"43 1","pages":"20"},"PeriodicalIF":8.1,"publicationDate":"2023-03-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10015716/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9483683","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Cassandra Margotta, Paola Fabbrizio, Marco Ceccanti, Chiara Cambieri, Gabriele Ruffolo, Jessica D'Agostino, Maria Chiara Trolese, Pierangelo Cifelli, Veronica Alfano, Christian Laurini, Silvia Scaricamazza, Alberto Ferri, Gianni Sorarù, Eleonora Palma, Maurizio Inghilleri, Caterina Bendotti, Giovanni Nardo
{"title":"Immune-mediated myogenesis and acetylcholine receptor clustering promote a slow disease progression in ALS mouse models.","authors":"Cassandra Margotta, Paola Fabbrizio, Marco Ceccanti, Chiara Cambieri, Gabriele Ruffolo, Jessica D'Agostino, Maria Chiara Trolese, Pierangelo Cifelli, Veronica Alfano, Christian Laurini, Silvia Scaricamazza, Alberto Ferri, Gianni Sorarù, Eleonora Palma, Maurizio Inghilleri, Caterina Bendotti, Giovanni Nardo","doi":"10.1186/s41232-023-00270-w","DOIUrl":"https://doi.org/10.1186/s41232-023-00270-w","url":null,"abstract":"<p><strong>Background: </strong>Amyotrophic lateral sclerosis (ALS) is a heterogeneous disease in terms of onset and progression rate. This may account for therapeutic clinical trial failure. Transgenic SOD1G93A mice on C57 or 129Sv background have a slow and fast disease progression rate, mimicking the variability observed in patients. Based on evidence inferring the active influence of skeletal muscle on ALS pathogenesis, we explored whether dysregulation in hindlimb skeletal muscle reflects the phenotypic difference between the two mouse models.</p><p><strong>Methods: </strong>Ex vivo immunohistochemical, biochemical, and biomolecular methodologies, together with in vivo electrophysiology and in vitro approaches on primary cells, were used to afford a comparative and longitudinal analysis of gastrocnemius medialis between fast- and slow-progressing ALS mice.</p><p><strong>Results: </strong>We reported that slow-progressing mice counteracted muscle denervation atrophy by increasing acetylcholine receptor clustering, enhancing evoked currents, and preserving compound muscle action potential. This matched with prompt and sustained myogenesis, likely triggered by an early inflammatory response switching the infiltrated macrophages towards a M2 pro-regenerative phenotype. Conversely, upon denervation, fast-progressing mice failed to promptly activate a compensatory muscle response, exhibiting a rapidly progressive deterioration of muscle force.</p><p><strong>Conclusions: </strong>Our findings further pinpoint the pivotal role of skeletal muscle in ALS, providing new insights into underestimated disease mechanisms occurring at the periphery and providing useful (diagnostic, prognostic, and mechanistic) information to facilitate the translation of cost-effective therapeutic strategies from the laboratory to the clinic.</p>","PeriodicalId":13588,"journal":{"name":"Inflammation and Regeneration","volume":"43 1","pages":"19"},"PeriodicalIF":8.1,"publicationDate":"2023-03-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9996869/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9321109","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"JAK inhibition ameliorates bone destruction by simultaneously targeting mature osteoclasts and their precursors.","authors":"Shinya Yari, Junichi Kikuta, Hotaka Shigyo, Yu Miyamoto, Daisuke Okuzaki, Yuki Furusawa, Masafumi Minoshima, Kazuya Kikuchi, Masaru Ishii","doi":"10.1186/s41232-023-00268-4","DOIUrl":"https://doi.org/10.1186/s41232-023-00268-4","url":null,"abstract":"<p><strong>Background: </strong>Rheumatoid arthritis (RA) is characterized by chronic inflammation and resultant cartilage/bone destruction because of aberrantly activated osteoclasts. Recently, novel treatments with several Janus kinase (JAK) inhibitors have been shown to successfully ameliorate arthritis-related inflammation and bone erosion, although their mechanisms of action for limiting bone destruction remain unclear. Here, we examined the effects of a JAK inhibitor on mature osteoclasts and their precursors by intravital multiphoton imaging.</p><p><strong>Methods: </strong>Inflammatory bone destruction was induced by local injection of lipopolysaccharides into transgenic mice carrying reporters for mature osteoclasts or their precursors. Mice were treated with the JAK inhibitor, ABT-317, which selectively inhibits the activation of JAK1, and then subjected to intravital imaging with multiphoton microscopy. We also used RNA sequencing (RNA-Seq) analysis to investigate the molecular mechanism underlying the effects of the JAK inhibitor on osteoclasts.</p><p><strong>Results: </strong>The JAK inhibitor, ABT-317, suppressed bone resorption by blocking the function of mature osteoclasts and by targeting the migratory behaviors of osteoclast precursors to the bone surface. Further exhaustive RNA-Seq analysis demonstrated that Ccr1 expression on osteoclast precursors was suppressed in the JAK inhibitor-treated mice; the CCR1 antagonist, J-113863, altered the migratory behaviors of osteoclast precursors, which led to the inhibition of bone destruction under inflammatory conditions.</p><p><strong>Conclusions: </strong>This is the first study to determine the pharmacological actions by which a JAK inhibitor blocks bone destruction under inflammatory conditions; this inhibition is beneficial because of its dual effects on both mature osteoclasts and immature osteoclast precursors.</p>","PeriodicalId":13588,"journal":{"name":"Inflammation and Regeneration","volume":"43 1","pages":"18"},"PeriodicalIF":8.1,"publicationDate":"2023-03-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9983229/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10832015","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}