Thiranut Jaroonwitchawan, Hideki Arimochi, Yuki Sasaki, Chieko Ishifune, Hiroyuki Kondo, Kunihiro Otsuka, Shin-ichi Tsukumo and Koji Yasutomo : Stimulation of the farnesoid X receptor promotes M2 macrophage polarization., Frontiers in Immunology, Vol.14, 2023.
(要約)
This skewed polarization towards M2 macrophages by an FXR agonist was accompanied by increased expression of signaling molecules related to the retinoic acid receptor. Inhibition of the retinoic acid receptor suppressed FXR agonist-mediated M2 macrophage polarization, indicating that this polarization was, at least, partly dependent on the retinoic acid receptor pathway. These data demonstrate that FXR has a role in polarization toward M2 macrophages and suggest a possible therapeutic potential of FXR agonists in M2 macrophage-related conditions.
Yuki Sasaki, Hideki Arimochi, Kunihiro Otsuka, Hiroyuki Kondo, Shin-ichi Tsukumo and Koji Yasutomo : Blockade of the CXCR3/CXCL10 axis ameliorates inflammation caused by immunoproteasome dysfunction., JCI Insight, Vol.7, No.7, 2022.
(要約)
Immunoproteasomes regulate the degradation of ubiquitin-coupled proteins and generate peptides that are preferentially presented by MHC class I. Mutations in immunoproteasome subunits lead to immunoproteasome dysfunction, which causes proteasome-associated autoinflammatory syndromes (PRAAS) characterized by nodular erythema and partial lipodystrophy. It remains unclear, however, how immunoproteasome dysfunction leads to inflammatory symptoms. Here, we established mice harboring a mutation in Psmb8 (Psmb8-KI mice) and addressed this question. Psmb8-KI mice showed higher susceptibility to imiquimod-induced skin inflammation (IMS). Blockade of IL-6 or TNF-α partially suppressed IMS in both control and Psmb8-KI mice, but there was still more residual inflammation in the Psmb8-KI mice than in the control mice. DNA microarray analysis showed that treatment of J774 cells with proteasome inhibitors increased the expression of the Cxcl9 and Cxcl10 genes. Deficiency in Cxcr3, the gene encoding the receptor of CXCL9 and CXCL10, in control mice did not change IMS susceptibility, while deficiency in Cxcr3 in Psmb8-KI mice ameliorated IMS. Taken together, these findings demonstrate that this mutation in Psmb8 leads to hyperactivation of the CXCR3 pathway, which is responsible for the increased susceptibility of Psmb8-KI mice to IMS. These data suggest the CXCR3/CXCL10 axis as a new molecular target for treating PRAAS.
Michittra Boonchan, Hideki Arimochi, Kunihiro Otsuka, Tomoko Kobayashi, Hisanori Uehara, Thiranut Jaroonwitchawan, Yuki Sasaki, Shin-ichi Tsukumo and Koji Yasutomo : Necroptosis protects against exacerbation of acute pancreatitis., Cell Death & Disease, Vol.12, No.6, 601, 2021.
(要約)
mice exhibit weight loss, edematous pancreatitis, necrotizing pancreatitis, and acinar cell dedifferentiation in response to tissue damage. Genetic deletion of Mlkl resulted in downregulation of the antiapoptotic genes Bclxl and Cflar in association with increases in the numbers of apoptotic cells, as detected by TUNEL assay. These findings suggest that RIPK3 and MLKL-mediated necroptosis exerts protective effects in AP and caution against the use of necroptosis inhibitors for AP treatment.
Yuki Sasaki, Kunihiro Otsuka, Hideki Arimochi, Shin-ichi Tsukumo and Koji Yasutomo : Distinct Roles of IL-1 and IL-18 in NLRC4-Induced Autoinflammation., Frontiers in Immunology, Vol.11, 591713, 2020.
(要約)
The NLRC4 inflammasome assembles in response to detection of bacterial invasion, and NLRC4 activation leads to the production of IL-1 and IL-18 together with pyroptosis-mediated cell death. Missense activating mutations in cause autoinflammatory disorders whose symptoms are distinctly dependent on the site of mutation and other aspects of the genetic background. To determine the involvement of IL-1 and IL-18 in the inflammation induced by mutation, we depleted IL-1 , IL-18, or both cytokines in Nlrc4-transgenic mice in which mutant is expressed under the MHC class II promoter (Nlrc4-H443P-Tg mice). The deletion of the or gene in Nlrc4-H443P-Tg mice reduced the neutrophil numbers in the spleen, and mice with deletion of both genes had an equivalent number of neutrophils compared to wild-type mice. Deletion of ameliorated but did not eliminate bone marrow hyperplasia, while mice deficient in showed no bone marrow hyperplasia. In contrast, tail bone deformity remained in the presence of deficiency, but deficiency completely abolished bone deformity. The decreased bone density in Nlrc4-H443P-Tg mice was counteracted by but not deficiency. Our results demonstrate the distinct effects of IL-1 and IL-18 on NLRC4-induced inflammation among tissues, which suggests that blockers for each cytokine should be utilized depending on the site of inflammation.
Hideki Arimochi, Yuki Sasaki, Akiko Kitamura and Koji Yasutomo : Differentiation of preadipocytes and mature adipocytes requires PSMB8., Scientific Reports, Vol.6, 26791, 2016.
(要約)
The differentiation of adipocytes is tightly regulated by a variety of intrinsic molecules and also by extrinsic molecules produced by adjacent cells. Dysfunction of adipocyte differentiation causes lipodystrophy, which impairs glucose and lipid homeostasis. Although dysfunction of immunoproteasomes causes partial lipodystrophy, the detailed molecular mechanisms remain to be determined. Here, we demonstrate that Psmb8, a catalytic subunit for immunoproteasomes, directly regulates the differentiation of preadipocytes and additionally the differentiation of preadipocytes to mature adipocytes. Psmb8(-/-) mice exhibited slower weight gain than wild-type mice, and this was accompanied by reduced adipose tissue volume and smaller size of mature adipocytes compared with controls. Blockade of Psmb8 activity in 3T3-L1 cells disturbed the differentiation to mature adipocytes. Psmb8(-/-) mice had fewer preadipocyte precursors, fewer preadipocytes and a reduced ability to differentiate preadipocytes toward mature adipocytes. Our data demonstrate that Psmb8-mediated immunoproteasome activity is a direct regulator of the differentiation of preadipocytes and their ultimate maturation.
Akiko Kitamura, Yuki Sasaki, Takaya Abe, Hirotsugu Kano and Koji Yasutomo : An inherited mutation in NLRC4 causes autoinflammation in human and mice., The Journal of Experimental Medicine, Vol.211, No.12, 2385-2396, 2014.
(要約)
Autoinflammatory syndromes cause sterile inflammation in the absence of any signs of autoimmune responses. Familial cold autoinflammatory syndrome (FCAS) is characterized by intermittent episodes of rash, arthralgia, and fever after exposure to cold stimuli. We have identified a missense mutation in the NLRC4 gene in patients with FCAS. NLRC4 has been known as a crucial sensor for several Gram-negative intracellular bacteria. The mutation in NLRC4 in FCAS patients promoted the formation of NLRC4-containing inflammasomes that cleave procaspase-1 and increase production of IL-1. Transgenic mice that expressed mutant Nlrc4 under the invariant chain promoter developed dermatitis and arthritis. Inflammation within tissues depended on IL-1-mediated production of IL-17A from neutrophils but not from T cells. Our findings reveal a previously unrecognized link between NLRC4 and a hereditary autoinflammatory disease and highlight the importance of NLRC4 not only in the innate immune response to bacterial infections but also in the genesis of inflammatory diseases.
Chieko Ishifune, Satoshi Maruyama, Yuki Sasaki, Hideo Yagita, Katsuto Hozumi, Taisuke Tomita, Kenji Kishihara and Koji Yasutomo : Differentiation of CD11c+ CX3CR1+ cells in the small intestine requires Notch signaling., Proceedings of the National Academy of Sciences of the United States of America, Vol.111, No.16, 5986-5991, 2014.
(要約)
The gastrointestinal tract comes into direct contact with environmental agents, including bacteria, viruses, and foods. Intestine-specific subsets of immune cells maintain gut homeostasis by continuously sampling luminal antigens and maintaining immune tolerance. CD11c(+)CX3CR1(+) cells sample luminal antigens in the small intestine and contribute to the trafficking of bacteria to lymph nodes under dysbiotic conditions. The molecular mechanisms crucial for the differentiation of CD11c(+)CX3CR1(+) cells remain unclear. Here we demonstrate that the Notch1- or Notch2-Rbpj axis is essential for the development of CD11c(+)CX3CR1(+) cells. In mice in which Rbpj or Notch1 and Notch2 were deleted from CD11c(+) cells, there was a deficit of CD11c(+)CX3CR1(+) cells and an accumulation of CD11c(low)CX3CR1(+) cells. The CD11c(low)CX3CR1(+) cells could not differentiate to CD11c(+)CX3CR1(+) cells, suggesting that CD11c(low)CX3CR1(+) cells represent a lineage distinct from CD11c(+)CX3CR1(+) cells. These data indicate that Notch signaling is essential for lineage fixation of intestinal CD11c(+)CX3CR1(+) cells.
(キーワード)
Animals / Antigens, CD11c / Cell Count / Cell Differentiation / Immunoglobulin J Recombination Signal Sequence-Binding Protein / Intestine, Small / Mice / Mice, Inbred C57BL / Receptors, Chemokine / Receptors, Notch / Signal Transduction
Hideki Arimochi, Yuki Sasaki, Akiko Kitamura and Koji Yasutomo : Dysfunctional immunoproteasomes in autoinflammatory diseases, Inflammation and Regeneration, Vol.36, No.13, May 2016.
Hideki Arimochi, Yuki Sasaki and Koji Yasutomo : Dysfunction of PSMB8 suppresses the maturation and anti-bacterial responses of adipocytes, 第45回日本免疫学会学術集会, Dec. 2016.
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Yuki Sasaki, Hideki Arimochi and Koji Yasutomo : Cytokines regulation of autoinflammation caused by dysfunctions of immunoproteasomes, 第45回日本免疫学会学術集会, Dec. 2016.