Masashi Ikutani

Publications (8)35.94 Total impact

• Article: The RP105/MD-1 complex is indispensable for TLR4/MD-2-dependent proliferation and IgM-secreting plasma cell differentiation of marginal zone B cells.

  Yoshinori Nagai, Tsutomu Yanagibashi, Yasuharu Watanabe, Masashi Ikutani, Ai Kariyone, Shoichiro Ohta, Yoshikatsu Hirai, Masao Kimoto, Kensuke Miyake, Kiyoshi Takatsu
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  ABSTRACT: Marginal zone (MZ) B cells mount rapid T-cell-independent (T-I) immune responses against microbial components such as LPS. While Toll-like receptor 4 (TLR4) is essential for LPS responses, MZ B cells uniquely express high levels of another LPS sensor Radioprotective 105 (RP105). However, little is known about how RP105 is used by MZ B cells. In this study, we investigated TLR4- or RP105-dependent MZ B cell responses by utilizing agonistic monoclonal antibodies (mAbs) to each receptor. Cross-linking TLR4 and RP105 at the same time with the mAbs induced robust IgM-secreting plasma cell generation as lipid A moiety of LPS. In contrast, stimulation with either mAb alone did not elicit such responses. RP105-deficient MZ B cells failed to produce IgM-secreting plasma cells in response to lipid A. TLR4 or lipid A stimulation of MZ B cells up-regulated their B lymphocyte-induced maturation protein 1 (Blimp-1) and X-box-binding protein 1 (Xbp-1) mRNA expression. RP105 stimulation alone did not give these responses and in fact decreased TLR4-mediated their expression. Compared with wild-type (WT) MZ B cells, RP105-deficient MZ B cells exhibited increased levels of Blimp-1 and Xbp-1 mRNA expression in response to lipid A. Lipid A or TLR4 plus RP105 stimulation induced massive proliferation and expression of Bcl-xL and c-Myc in WT but not RP105-deficient MZ B cells. These responses contributed to TLR4-mediated anti-apoptotic responses in MZ B cells. Thus, RP105 contributes in a unique way to the TLR4-dependent survival, proliferation and plasma cell generation of MZ B cells.
  International Immunology 02/2012; 24(6):389-400. · 3.41 Impact Factor
• Article: Identification of innate IL-5-producing cells and their role in lung eosinophil regulation and antitumor immunity.

  Masashi Ikutani, Tsutomu Yanagibashi, Masaru Ogasawara, Koichi Tsuneyama, Seiji Yamamoto, Yuichi Hattori, Taku Kouro, Atsuko Itakura, Yoshinori Nagai, Satoshi Takaki, Kiyoshi Takatsu
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  ABSTRACT: IL-5 is involved in a number of immune responses such as helminth infection and allergy. IL-5 also plays roles in innate immunity by maintaining B-1 B cells and mucosal IgA production. However, the identity of IL-5-producing cells has not been unambiguously characterized. In this report, we describe the generation of an IL-5 reporter mouse and identify IL-5-producing non-T lymphoid cells that reside in the intestine, peritoneal cavity, and lungs in naive mice. They share many characteristics with natural helper cells, nuocytes, and Ih2 cells, including surface Ags and responsiveness to cytokines. However, these phenotypes do not completely overlap with any particular one of these cell types. Innate non-T IL-5-producing cells localized most abundantly in the lung and proliferated and upregulated IL-5 production in response to IL-25 and IL-33. IL-33 was more effective than IL-25. These cells contribute to maintaining sufficient numbers of lung eosinophils and are important for eosinophil recruitment mediated by IL-25 and IL-33. Given that eosinophils are shown to possess antitumor activity, we studied lung tumor metastasis and showed that innate IL-5-producing cells were increased in response to tumor invasion, and their regulation of eosinophils is critical to suppress tumor metastasis. Genetic blockade or neutralization of IL-5 impaired eosinophil recruitment into the lung and resulted in increased tumor metastasis. Conversely, exogenous IL-5 treatment resulted in suppressed tumor metastasis and augmented eosinophil infiltration. These newly identified innate IL-5-producing cells thus play a role in tumor surveillance through lung eosinophils and may contribute to development of novel immunotherapies for cancer.
  The Journal of Immunology 12/2011; 188(2):703-13. · 5.79 Impact Factor
• Article: Serum soluble MD-1 levels increase with disease progression in autoimmune prone MRL(lpr/lpr) mice.

  Sumiyo Sasaki, Yoshinori Nagai, Tsutomu Yanagibashi, Yasuharu Watanabe, Masashi Ikutani, Ai Kariyone, Koichi Tsuneyama, Yoshikatsu Hirai, Kiyoshi Takatsu
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  ABSTRACT: MD-1 is a secreted protein that forms a complex with radioprotective 105 (RP105) and this complex plays a crucial role in lipopolysaccharide (LPS) recognition by B cells. Disease progression is known to improve in RP105-deficient lupus-prone MRL(lpr/lpr) mice. Furthermore, a soluble form of the homologous MD-2 protein is present in the plasma of septic patients and can opsonize gram-negative bacteria in cooperation with Toll-like receptor (TLR) 4. We have now established a flow cytometry-based assay to detect the soluble form of murine MD-1 (sMD-1) and explored potential roles in autoimmunity. The assay was quantitative and validated with sera from MD-1-deficient mice. Interestingly, heat-inactivated murine serum diminished the ability of sMD-1 to bind RP105. The sMD-1 was secreted by bone marrow-derived macrophages from C57BL/6 mice. Autoimmune prone MRL(lpr/lpr) mice had higher levels of sMD-1 than control MRL(+/+) mice, and levels markedly increased with disease progression. Expression of MD-1 but not MD-2 mRNA increased with age in the liver and kidney of MRL(lpr/lpr) mice. Finally, immunohistochemical analyses revealed that MD-1 was present in infiltrated macrophages within perivascular lesions of the MRL(lpr/lpr) kidney. This correlation suggests that sMD-1 may contribute to pathogenesis in this autoimmune disease model.
  Molecular Immunology 11/2011; 49(4):611-20. · 2.90 Impact Factor
• Article: Telmisartan improves insulin resistance and modulates adipose tissue macrophage polarization in high-fat-fed mice.

  Shiho Fujisaka, Isao Usui, Yukiko Kanatani, Masashi Ikutani, Ichiro Takasaki, Koichi Tsuneyama, Yoshiaki Tabuchi, Agussalim Bukhari, Yu Yamazaki, Hikari Suzuki, Satoko Senda, Aminuddin Aminuddin, Yoshinori Nagai, Kiyoshi Takatsu, Masashi Kobayashi, Kazuyuki Tobe
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  ABSTRACT: Diet-induced obesity is reported to induce a phenotypic switch in adipose tissue macrophages from an antiinflammatory M2 state to a proinflammatory M1 state. Telmisartan, an angiotensin II type 1 receptor blocker and a peroxisome proliferator-activated receptor-γ agonist, reportedly has more beneficial effects on insulin sensitivity than other angiotensin II type 1 receptor blockers. In this study, we studied the effects of telmisartan on the adipose tissue macrophage phenotype in high-fat-fed mice. Telmisartan was administered for 5 wk to high-fat-fed C57BL/6 mice. Insulin sensitivity, macrophage infiltration, and the gene expressions of M1 and M2 markers in visceral adipose tissues were then examined. An insulin- or a glucose-tolerance test showed that telmisartan treatment improved insulin resistance, decreasing the body weight gain, visceral fat weight, and adipocyte size without affecting the amount of energy intake. Telmisartan reduced the mRNA expression of CD11c and TNF-α, M1 macrophage markers, and significantly increased the expressions of M2 markers, such as CD163, CD209, and macrophage galactose N-acetyl-galactosamine specific lectin (Mgl2), in a quantitative RT-PCR analysis. A flow cytometry analysis showed that telmisartan decreased the number of M1 macrophages in visceral adipose tissues. In conclusion, telmisartan improves insulin sensitivity and modulates adipose tissue macrophage polarization to an antiinflammatory M2 state in high-fat-fed mice.
  Endocrinology 03/2011; 152(5):1789-99. · 4.46 Impact Factor
• Source

  Available from: Yoshinori Nagai

  Article: Regulatory mechanisms for adipose tissue M1 and M2 macrophages in diet-induced obese mice.

  Shiho Fujisaka, Isao Usui, Agussalim Bukhari, Masashi Ikutani, Takeshi Oya, Yukiko Kanatani, Koichi Tsuneyama, Yoshinori Nagai, Kiyoshi Takatsu, Masaharu Urakaze, Masashi Kobayashi, Kazuyuki Tobe
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  ABSTRACT: To characterize the phenotypic changes of adipose tissue macrophages (ATMs) under different conditions of insulin sensitivity. The number and the expressions of marker genes for M1 and M2 macrophages from mouse epididymal fat tissue were analyzed using flow cytometry after the mice had been subjected to a high-fat diet (HFD) and pioglitazone treatment. Most of the CD11c-positive M1 macrophages and the CD206-positive M2 macrophages in the epididymal fat tissue were clearly separated using flow cytometry. The M1 and M2 macrophages exhibited completely different gene expression patterns. Not only the numbers of M1 ATMs and the expression of M1 marker genes, such as tumor necrosis factor-alpha and monocyte chemoattractant protein-1, but also the M1-to-M2 ratio were increased by an HFD and decreased by subsequent pioglitazone treatment, suggesting the correlation with whole-body insulin sensitivity. We also found that the increased number of M2 ATMs after an HFD was associated with the upregulated expression of interleukin (IL)-10, an anti-inflammatory Th2 cytokine, in the adipocyte fraction as well as in adipose tissue. The systemic overexpression of IL-10 by an adenovirus vector increased the expression of M2 markers in adipose tissue. M1 and M2 ATMs constitute different subsets of macrophages. Insulin resistance is associated with both the number of M1 macrophages and the M1-to-M2 ratio. The increased expression of IL-10 after an HFD might be involved in the increased recruitment of M2 macrophages.
  Diabetes 09/2009; 58(11):2574-82. · 8.29 Impact Factor
• Article: Expression of IL-5Ralpha on B-1 cell progenitors in mouse fetal liver and involvement of Bruton's tyrosine kinase in their development.

  Taku Kouro, Masashi Ikutani, Ai Kariyone, Kiyoshi Takatsu
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  ABSTRACT: B-1 cells are a subset of B cells responsible for the production of natural antibodies. Although the amount of natural antibody is tightly regulated, how this regulation occurs remains unknown. We examined the expression of IL-5 receptor, a cytokine receptor critical for homeostatic proliferation of B-1 cells, on B-1 cell progenitors in the fetal liver. We identified B-1 progenitors expressing low levels of IL-5 receptor alpha chain (IL-5Ralpha) and eosinophil progenitors expressing higher levels of IL-5Ralpha in the fetal liver. Moreover, the number of these B-1 progenitors were significantly reduced in the fetuses of mice deficient in Bruton's tyrosine kinase (Btk), even though IL-5 and thymic stroma lymphopoietin signaling are intact in early B lineage cells in Btk-deficient mice. These data suggest that IL-5 is possibly involved in B-1 cell development and an uncharacterized, Btk-dependent regulatory signaling pathway is involved in unexpectedly early stages of B-1 cell differentiation.
  Immunology letters 05/2009; 123(2):169-78. · 2.91 Impact Factor
• Article: Interleukin 5 plays an essential role in elicitation of contact sensitivity through dual effects on eosinophils and B-1 cells.

  Atsuko Itakura, Yuji Kikuchi, Taku Kouro, Masashi Ikutani, Satoshi Takaki, Philip W Askenase, Kiyoshi Takatsu
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  ABSTRACT: Elicitation of contact sensitivity (CS) depends on B-1-cell-derived antigen-specific immunoglobulin M (IgM) antibodies that recruit CS effector T cells into the local tissue, which is followed by infiltration of antigen-nonspecific mononuclear cells and polymorphonuclear cells, such as neutrophils and eosinophils. In this study, we investigated the role of interleukin (IL)-5, which has broad effects on both eosinophils and B-1 cells, in elicitation of CS. IL-5 receptor alpha-chain-deficient (IL-5Ralpha-/-) mice and IL-5Ralpha+/+ mice were contact sensitized with oxazolone hapten. Four days later, mice were challenged with the same hapten, and ear swelling responses were measured at 24 h after challenge. Eosinophil infiltration into the local tissue was determined by examination of skin histology and eosinophil peroxidase activity. To investigate the role of IL-5 in B-1 cell activation, the number of oxazolone-specific IgM-producing cells in the spleen was determined by enzyme-linked immunospot assay. Ear swelling responses in IL-5Ralpha-/- mice were about half of those in IL-5Ralpha+/+ mice, and nearly no eosinophil infiltration was observed in IL-5Ralpha-/- mouse skin. Eosinophil peroxidase activity in the sensitized and challenged IL-5Ralpha-/- mice was about 11 times less than that in immunized IL-5Ralpha+/+ mice. Contact sensitization significantly increased in numbers of oxazolne-specific IgM-producing cells in IL-5Ralpha+/+ mouse spleen, but not in IL-5Ralpha-/- mouse spleen. We conclude that IL-5-dependent activation of eosinophils and B-1 cells is necessary for induction and elicitation of CS. These findings provide a new insight into complicated mechanisms of CS elicitation and suggest a novel role of IL-5 in the regulation of immune responses.
  International Archives of Allergy and Immunology 02/2006; 140 Suppl 1:8-16. · 2.40 Impact Factor
• Article: Partitioning of rearranged Ig genes by mutation analysis demonstrates D-D fusion and V gene replacement in the expressed human repertoire.

  Andrew M Collins, Masashi Ikutani, Daniela Puiu, Gregory A Buck, Aradhita Nadkarni, Bruno Gaeta
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  ABSTRACT: The accurate partitioning of Ig H chain V(H)DJ(H) junctions and L chain V(L)J(L) junctions is problematic. We have developed a statistical approach for the partitioning of such sequences, by analyzing the distribution of point mutations between a determined V gene segment and putative Ig regions. The establishment of objective criteria for the partitioning of sequences between V(H), D, and J(H) gene segments has allowed us to more carefully analyze intervening putative nontemplated (N) nucleotides. An analysis of 225 IgM H chain sequences, with five or fewer V mutations, led to the alignment of 199 sequences. Only 5.0% of sequences lacked N nucleotides at the V(H)D junction (N1), and 10.6% at the DJ(H) junction (N2). Long N regions (>9 nt) were seen in 20.6% of N1 regions and 17.1% of N2 regions. Using a statistical analysis based upon known features of N addition, and mutation analysis, two of these N regions aligned with D gene segments, and a third aligned with an inverted D gene segment. Nine additional sequences included possible alignments with a second D segment. Four of the remaining 40 long N1 regions included 5' sequences having six or more matches to V gene end motifs, which may be the result of V gene replacement. Such sequences were not seen in long N2 regions. The long N regions frequently seen in the expressed repertoire of human Ig gene rearrangements can therefore only partly be explained by V gene replacement and D-D fusion.
  The Journal of Immunology 02/2004; 172(1):340-8. · 5.79 Impact Factor