Publications by authors named "Toshiyuki Takai"

153 Publications

Astrocytic phagocytosis is a compensatory mechanism for microglial dysfunction.

EMBO J 2020 11 22;39(22):e104464. Epub 2020 Sep 22.

Department of Functional Anatomy and Neuroscience, Nagoya University Graduate School of Medicine, Nagoya, Japan.

Microglia are the principal phagocytes that clear cell debris in the central nervous system (CNS). This raises the question, which cells remove cell debris when microglial phagocytic activity is impaired. We addressed this question using Siglech mice, which enable highly specific ablation of microglia. Non-microglial mononuclear phagocytes, such as CNS-associated macrophages and circulating inflammatory monocytes, did not clear microglial debris. Instead, astrocytes were activated, exhibited a pro-inflammatory gene expression profile, and extended their processes to engulf microglial debris. This astrocytic phagocytosis was also observed in Irf8-deficient mice, in which microglia were present but dysfunctional. RNA-seq demonstrated that even in a healthy CNS, astrocytes express TAM phagocytic receptors, which were the main astrocytic phagocytic receptors for cell debris in the above experiments, indicating that astrocytes stand by in case of microglial impairment. This compensatory mechanism may be important for the maintenance or prolongation of a healthy CNS.
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http://dx.doi.org/10.15252/embj.2020104464DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7667883PMC
November 2020

Nogo receptor antagonist LOTUS exerts suppression on axonal growth-inhibiting receptor PIR-B.

J Neurochem 2020 11 13;155(3):285-299. Epub 2020 Apr 13.

Molecular Medical Bioscience Laboratory, Department of Medical Life Science, Yokohama City University Graduate School of Medical Life Science, Yokohama, Japan.

Damaged axons in the adult mammalian central nervous system have a restricted regenerative capacity mainly because of Nogo protein, which is a major myelin-associated axonal growth inhibitor with binding to both receptors of Nogo receptor-1 (NgR1) and paired immunoglobulin-like receptor (PIR)-B. Lateral olfactory tract usher substance (LOTUS) exerts complete suppression of NgR1-mediated axonal growth inhibition by antagonizing NgR1. However, the regulation of PIR-B functions in neurons remains unknown. In this study, protein-protein interactions analyses found that LOTUS binds to PIR-B and abolishes Nogo-binding to PIR-B completely. Reverse transcription-polymerase chain reaction and immunocytochemistry revealed that PIR-B is expressed in dorsal root ganglions (DRGs) from wild-type and Ngr1-deficient mice (male and female). In these DRG neurons, Nogo induced growth cone collapse and neurite outgrowth inhibition, but treatment with the soluble form of LOTUS completely suppressed them. Moreover, Nogo-induced growth cone collapse and neurite outgrowth inhibition in Ngr1-deficient DRG neurons were neutralized by PIR-B function-blocking antibodies, indicating that these Nogo-induced phenomena were mediated by PIR-B. Our data show that LOTUS negatively regulates a PIR-B function. LOTUS thus exerts an antagonistic action on both receptors of NgR1 and PIR-B. This may lead to an improvement in the defective regeneration of axons following injury.
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http://dx.doi.org/10.1111/jnc.15013DOI Listing
November 2020

Dual functions of angiopoietin-like protein 2 signaling in tumor progression and anti-tumor immunity.

Genes Dev 2019 12 14;33(23-24):1641-1656. Epub 2019 Nov 14.

Department of Molecular Genetics, Graduate school of Medical science, Kumamoto University, Kumamoto 860-8556, Japan.

Angiopoietin-like protein 2 (ANGPTL2) is a secreted glycoprotein homologous to angiopoietins. Previous studies suggest that tumor cell-derived ANGPTL2 has tumor-promoting function. Here, we conducted mechanistic analysis comparing ANGPTL2 function in cancer progression in a murine syngeneic model of melanoma and a mouse model of translocation renal cell carcinoma (tRCC). ANGPTL2 deficiency in tumor cells slowed tRCC progression, supporting a tumor-promoting role. However, systemic ablation of ANGPTL2 accelerated tRCC progression, supporting a tumor-suppressing role. The syngeneic model also demonstrated a tumor-suppressing role of ANGPTL2 in host tumor microenvironmental cells. Furthermore, the syngeneic model showed that PDGFRα fibroblasts in the tumor microenvironment express abundant ANGPTL2 and contribute to tumor suppression. Moreover, host ANGPTL2 facilitates CD8 T-cell cross-priming and enhances anti-tumor immune responses. Importantly, ANGPTL2 activates dendritic cells through PIR-B-NOTCH signaling and enhances tumor vaccine efficacy. Our study provides strong evidence that ANGPTL2 can function in either tumor promotion or suppression, depending on what cell type it is expressed in.
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http://dx.doi.org/10.1101/gad.329417.119DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6942048PMC
December 2019

Identification of Quantitative Trait Loci for the Concentrations of Phenylpropanoid Glycosides in Brown Rice.

ACS Omega 2019 Oct 7;4(17):17317-17325. Epub 2019 Oct 7.

Institute of Crop Science, NARO, 2-1-18 Kannondai, Tsukuba, Ibaraki 305-8518, Japan.

Rice ( L.) is a staple food for most of the world's population, as it is eaten by nearly half of its inhabitants. Phenylpropanoid glycosides derived from plants have various biomedical effects. The comparison of the concentrations of the four major phenylpropanoid glycosides in brown rice, i.e., 6--feruloylsucrose (), 3',6-di--sinapoylsucrose (), 3'--sinapoyl-6--feruloylsucrose (), and 3',6-di--feruloylsucrose (), between a conventional -type cultivar Koshihikari and a high-yielding -type cultivar Takanari revealed that they were 57-162% higher in Koshihikari than in Takanari. To identify quantitative trait loci (QTLs) for the concentrations of these compounds (-), reciprocal chromosome segment substitution lines derived from a cross between Koshihikari and Takanari were analyzed. We identified QTLs for the concentrations of compound on chromosome 2 and of compound on chromosome 4 in the reciprocal genetic background. The concentrations of these compounds were increased by the Koshihikari alleles and decreased by the Takanari alleles. Therefore, the favorable alleles of Koshihikari are available to ameliorate the lower concentrations of compounds and in Takanari. The combinations of QTLs identified in the present study together with those of other biologically active compounds make it possible to breed health beneficial cultivars.
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http://dx.doi.org/10.1021/acsomega.9b02030DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6811851PMC
October 2019

Abl family tyrosine kinases govern IgG extravasation in the skin in a murine pemphigus model.

Nat Commun 2019 09 30;10(1):4432. Epub 2019 Sep 30.

Department of Dermatology, Kyoto University Graduate School of Medicine, Kyoto, Japan.

The pathway of homeostatic IgG extravasation is not fully understood, in spite of its importance for the maintenance of host immunity, the management of autoantibody-mediated disorders, and the use of antibody-based biologics. Here we show in a murine model of pemphigus, a prototypic cutaneous autoantibody-mediated disorder, that blood-circulating IgG extravasates into the skin in a time- and dose-dependent manner under homeostatic conditions. This IgG extravasation is unaffected by depletion of Fcγ receptors, but is largely attenuated by specific ablation of dynamin-dependent endocytic vesicle formation in blood endothelial cells (BECs). Among dynamin-dependent endocytic vesicles, IgG co-localizes well with caveolae in cultured BECs. An Abl family tyrosine kinase inhibitor imatinib, which reduces caveolae-mediated endocytosis, impairs IgG extravasation in the skin and attenuates the murine pemphigus manifestations. Our study highlights the kinetics of IgG extravasation in vivo, which might be a clue to understand the pathological mechanism of autoantibody-mediated autoimmune disorders.
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http://dx.doi.org/10.1038/s41467-019-12232-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6769004PMC
September 2019

Genetic architecture of leaf photosynthesis in rice revealed by different types of reciprocal mapping populations.

J Exp Bot 2019 10;70(19):5131-5144

Graduate School of Agriculture, Tokyo University of Agriculture and Technology, Fuchu, Tokyo, Japan.

The improvement of leaf net photosynthetic rate (An) is a major challenge in enhancing crop productivity. However, the genetic control of An among natural genetic accessions is still poorly understood. The high-yielding indica cultivar Takanari has the highest An of all rice cultivars, 20-30% higher than that of the high-quality japonica cultivar Koshihikari. By using reciprocal backcross inbred lines and chromosome segment substitution lines derived from a cross between Takanari and Koshihikari, we identified three quantitative trait loci (QTLs) where the Takanari alleles enhanced An in plants with a Koshihikari genetic background and five QTLs where the Koshihikari alleles enhanced An in plants with a Takanari genetic background. Two QTLs were expressed in plants with both backgrounds (type I QTL). The expression of other QTLs depended strongly on genetic background (type II QTL). These beneficial alleles increased stomatal conductance, the initial slope of An versus intercellular CO2 concentration, or An at CO2 saturation. Pyramiding of these alleles consistently increased An. Some alleles positively affected biomass production and grain yield. These alleles associated with photosynthesis and yield can be a valuable tool in rice breeding programs via DNA marker-assisted selection.
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http://dx.doi.org/10.1093/jxb/erz303DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6793464PMC
October 2019

CTLA4-Ig Directly Inhibits Osteoclastogenesis by Interfering With Intracellular Calcium Oscillations in Bone Marrow Macrophages.

J Bone Miner Res 2019 09 16;34(9):1744-1752. Epub 2019 Jul 16.

Department of Orthopaedic Surgery, The University of Tokyo, Tokyo, Japan.

CTLA4-Ig (cytotoxic T-lymphocyte antigen 4-immunoglobulin; Abatacept) is a biologic drug for rheumatoid arthritis. CTLA4 binds to the CD80/86 complex of antigen-presenting cells and blocks the activation of T cells. Although previous reports showed that CTLA4-Ig directly inhibited osteoclast differentiation, the whole inhibitory mechanism of CTLA4-Ig for osteoclast differentiation is unclear. Bone marrow macrophages (BMMs) from WT mice were cultured with M-CSF and RANKL with or without the recombinant mouse chimera CTLA4-Ig. Intracellular calcium oscillations of BMMs with RANKL were detected by staining with calcium indicator fura-2 immediately after administration of CTLA4-Ig or after one day of treatment. Calcium oscillations were analyzed using Fc receptor gamma- (FcRγ-) deficient BMMs. CTLA4-Ig inhibited osteoclast differentiation and reduced the expression of the nuclear factor of activated T cells NFATc1 in BMMs in vitro. Calcium oscillations in BMMs were suppressed by CTLA4-Ig both immediately after administration and after one day of treatment. CTLA4-Ig did not affect osteoclastogenesis and did not cause remarkable changes in calcium oscillations in FcRγ-deficient BMMs. Finally, to analyze the effect of CTLA4-Ig in vivo, we used an LPS-induced osteolysis model. CTLA4-Ig suppressed LPS-induced bone resorption in WT mice, not in FcRγ-deficient mice. In conclusion, CTLA4-Ig inhibits intracellular calcium oscillations depending on FcRγ and downregulates NFATc1 expression in BMMs. © 2019 American Society for Bone and Mineral Research.
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http://dx.doi.org/10.1002/jbmr.3754DOI Listing
September 2019

Augmented ILT3/LILRB4 Expression of Peripheral Blood Antibody Secreting Cells in the Acute Phase of Kawasaki Disease.

Pediatr Infect Dis J 2019 04;38(4):431-438

Department of Pediatrics, Sendai Medical Center, Sendai, Japan.

Background: Kawasaki disease (KD) is an acute, systemic vasculitis syndrome that occurs in children. The clinical symptoms and epidemiologic features of KD strongly suggest that KD is triggered by unidentified infectious agents in genetically predisposed patients. In addition, a number of studies have described the role of B cells in the development of KD. To obtain a mechanistic insight into the humoral immune response of B-lineage cells in KD patients, we examined peripheral blood antibody secreting cells (ASCs) and inhibitory immunoreceptors, immunoglobulin-like transcript (ILT)/leukocyte immunoglobulin-like receptor (LILR), on each B cell subpopulation.

Methods: Eighteen Japanese KD patients and thirteen healthy control subjects were recruited for this study. Their peripheral blood mononuclear cells were examined by flow cytometry for the number of CD19 B cells, the size of each B cell subset and the expression of the inhibitory isoforms of ILT/LILR on the B cell subset.

Results: The frequency of CD19CD27 ASCs was significantly increased in the acute phase of KD and reduced after high-dose intravenous immunoglobulin (IVIG) treatment. Interestingly, while ILT2/LILRB1 expression was ubiquitously observed on every B cell/ASCs subset and the level was not significantly different after IVIG, ILT3/LILRB4 (B4) was uniquely expressed on only ASCs, and its expression was significantly decreased after IVIG.

Conclusions: In the acute phase of KD, the frequency of ASCs is high with augmented B4 expression, whereas it is lower with decreased B4 expression after IVIG. Further studies of B4 expression on ASCs in autoimmune and infectious diseases will be needed to confirm the significance of our findings.
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http://dx.doi.org/10.1097/INF.0000000000002259DOI Listing
April 2019

Gp49B is a pathogenic marker for auto-antibody-producing plasma cells in lupus-prone BXSB/Yaa mice.

Int Immunol 2019 05;31(6):397-406

Department of Experimental Immunology, Institute of Development, Aging and Cancer, Tohoku University, Sendai, Japan.

AbstractImmune homeostasis is critically regulated by the balance between activating and inhibitory receptors expressed on various immune cells such as T and B lymphocytes, and myeloid cells. The inhibitory receptors play a fundamental role in the immune checkpoint pathway, thus maintaining peripheral tolerance. We recently found that expression of leukocyte immunoglobulin-like receptor (LILR)B4, an inhibitory member of the human LILR family, is augmented in auto-antibody-producing plasmablasts/plasma cells of systemic lupus erythematosus (SLE) patients. However, the mechanism behind the 'paradoxical' up-regulation of this inhibitory receptor upon pathogenic antibody-secreting cells is yet to be known. To this end, in this study, we examined if glycoprotein 49B (gp49B), the murine counterpart of human LILRB4, is also elevated in auto-antibody-producing cells in several SLE mouse models, and tried to clarify the underlying mechanism. We found that gp49B is expressed on plasma cells of lupus-prone models but not of healthy C57BL/6 mice, and the level was positively correlated to the anti-double-stranded DNA IgG titer in serum. Gp49B genetic deletion, however, did not abolish the serum auto-antibodies or fully ameliorate the lethal glomerulonephritis, indicating that gp49B is not the sole regulator of lupus but a pathogenic element in the disease. We conclude that the elevated expression of this inhibitory receptor on pathogenic plasma cells was also relevant upon the murine SLE model. The mechanism of gp49B underlying the disease progression in lupus-prone mice has been discussed.
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http://dx.doi.org/10.1093/intimm/dxz017DOI Listing
May 2019

A novel QTL associated with rice canopy temperature difference affects stomatal conductance and leaf photosynthesis.

Breed Sci 2018 Jun 29;68(3):305-315. Epub 2018 Jun 29.

Institute of Crop Science, NARO, 2-1-2 Kannondai, Tsukuba, Ibaraki 305-8602, Japan.

Canopy temperature can be a good indicator of stomatal conductance. To understand the genetic basis of phenotypic differences in stomatal conductance between average and high-yielding rice ( L.) cultivars, we conducted a quantitative trait locus (QTL) analysis of canopy temperature. We developed reciprocal series of backcross inbred lines (BCF) derived from a cross between the average-yielding cultivar 'Koshihikari' and the high-yielding cultivar 'Takanari'. A stable QTL, (QTL for canopy temperature difference on chromosome 11) on the short arm of chromosome 11, accounted for 10.4 and 19.8% of the total phenotypic variance in the two lines; the 'Takanari' allele decreased the canopy temperature difference value. A chromosome segment substitution line carrying the Takanari showed a greater reduction in canopy temperature than 'Koshihikari', and had higher stomatal conductance and photosynthetic rate. These results suggest that is not only involved in canopy temperature, but is also involved in both stomatal conductance and photosynthetic rate.
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http://dx.doi.org/10.1270/jsbbs.17129DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6081301PMC
June 2018

Leukocyte mono-immunoglobulin-like receptor 8 (LMIR8)/CLM-6 is an FcRγ-coupled receptor selectively expressed in mouse tissue plasmacytoid dendritic cells.

Sci Rep 2018 05 29;8(1):8259. Epub 2018 May 29.

Atopy (Allergy) Research Center, Juntendo University Graduate School of Medicine, 2-1-1 Hongo, Bunkyo-ku, Tokyo, 113-8421, Japan.

Plasmacytoid dendritic cells (pDCs) produce large amounts of type-I interferon (IFN) in response to viral infection or self nucleic acids. Leukocyte mono-immunoglobulin-like receptor 8 (LMIR8), also called CMRF-35-like molecule-6 (CLM-6), is a putative activating receptor among mouse LMIR/CLM/CD300 members; however, the expression and function of LMIR8 remain unclear. Here, we characterize mouse LMIR8 as a pDC receptor. Analysis of Flag-tagged LMIR8-transduced bone marrow (BM)-derived mast cells demonstrated that LMIR8 can transmit an activating signal by interacting with immunoreceptor tyrosine-based activating motif (ITAM)-containing FcRγ. Flow cytometric analysis using a specific antibody for LMIR8 showed that LMIR8 expression was restricted to mouse pDCs residing in BM, spleen, or lymph node. FcRγ deficiency dampened surface expression of LMIR8 in mouse pDCs. Notably, LMIR8 was detected only in pDCs, irrespective of TLR9 stimulation, suggesting that LMIR8 is a suitable marker for pDCs in mouse tissues; LMIR8 is weakly expressed in Flt3 ligand-induced BM-derived pDCs (BMpDCs). Crosslinking of transduced LMIR8 in BMpDCs with anti-LMIR8 antibody did not induce IFN-α production, but rather suppressed TLR9-mediated production of IFN-α. Taken together, these observations indicate that LMIR8 is an FcRγ-coupled receptor selectively expressed in mouse tissue pDCs, which might suppress pDC activation through the recognition of its ligands.
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http://dx.doi.org/10.1038/s41598-018-25646-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5974347PMC
May 2018

Bone marrow PDGFRα+Sca-1+-enriched mesenchymal stem cells support survival of and antibody production by plasma cells in vitro through IL-6.

Int Immunol 2018 05;30(6):241-253

Department of Experimental Immunology, Institute of Development, Aging and Cancer, Tohoku University, Seiryo-machi, Sendai, Japan.

Plasma cells (PCs) acquiring long lifespans in the bone marrow (BM) play a pivotal role in the humoral arm of immunological memory. The PCs reside in a special BM niche and produce antibodies against past-encountered pathogens or vaccine components for a long time. In BM, cysteine-X-cysteine (CXC) chemokine receptor type 4 (CXCR4)-expressing PCs and myeloid cells such as dendritic cells are attracted to and held by CXC chemokine ligand 12 (CXCR12)-secreting stromal cells, where survival of the PCs is supported by soluble factors such as IL-6 and APRIL (a proliferation-inducing ligand) produced by neighboring myeloid cells. Although these stromal cells are also supposed to be involved in the support of the survival and antibody production, the full molecular mechanism has not been clarified yet. Here, we show that BM PDGFRα+Sca-1+-enriched mesenchymal stem cells (MSCs), which can contribute as stromal cells for hematopoietic stem cells, also support in vitro survival of and antibody production by BM PCs. IL-6 produced by MSCs was found to be involved in the support. Immunohistochemistry of BM sections suggested a co-localization of a minor population of PCs with PDGFRα+Sca-1+ MSCs in the BM. We also found that the sort-purified MSC preparation was composed of multiple cell groups with different gene expression profiles, as found on single-cell RNA sequencing, to which multiple roles in the in vitro PC support could be attributed.
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http://dx.doi.org/10.1093/intimm/dxy018DOI Listing
May 2018

The CD300e molecule in mice is an immune-activating receptor.

J Biol Chem 2018 03 22;293(10):3793-3805. Epub 2018 Jan 22.

From the Atopy (Allergy) Research Center, Juntendo University Graduate School of Medicine, 2-1-1 Hongo, Bunkyo-ku, Tokyo 113-8421,

CD300 molecules (CD300s) belong to paired activating and inhibitory receptor families, which mediate immune responses. Human CD300e (hCD300e) is expressed in monocytes and myeloid dendritic cells and transmits an immune-activating signal by interacting with DNAX-activating protein 12 (DAP12). However, the CD300e ortholog in mice (mCD300e) is poorly characterized. Here, we found that mCD300e is also an immune-activating receptor. We found that mCD300e engagement triggers cytokine production in mCD300e-transduced bone marrow-derived mast cells (BMMCs). Loss of DAP12 and another signaling protein, FcRγ, did not affect surface expression of transduced mCD300e, but abrogated mCD300e-mediated cytokine production in the BMMCs. Co-immunoprecipitation experiments revealed that mCD300e physically interacts with both FcRγ and DAP12, suggesting that mCD300e delivers an activating signal via these two proteins. Binding and reporter assays with the mCD300e extracellular domain identified sphingomyelin as a ligand of both mCD300e and hCD300e. Notably, the binding of sphingomyelin to mCD300e stimulated cytokine production in the transduced BMMCs in an FcRγ- and DAP12-dependent manner. Flow cytometric analysis with an mCD300e-specific Ab disclosed that mCD300e expression is highly restricted to CD115Ly-6C peripheral blood monocytes, corresponding to CD14CD16 human nonclassical and intermediate monocytes. Loss of FcRγ or DAP12 lowered the surface expression of endogenous mCD300e in the CD115Ly-6C monocytes. Stimulation with sphingomyelin failed to activate the CD115Ly-6C mouse monocytes, but induced hCD300e-mediated cytokine production in the CD14CD16 human monocytes. Taken together, these observations indicate that mCD300e recognizes sphingomyelin and thereby regulates nonclassical and intermediate monocyte functions through FcRγ and DAP12.
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http://dx.doi.org/10.1074/jbc.RA117.000696DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5846139PMC
March 2018

Identification of Secretory Leukoprotease Inhibitor As an Endogenous Negative Regulator in Allergic Effector Cells.

Front Immunol 2017 13;8:1538. Epub 2017 Nov 13.

Division of Immunology, Faculty of Medicine, Tohoku Medical and Pharmaceutical University, Sendai, Japan.

Mast cells, basophils, and eosinophils are central effectors in allergic inflammatory disorders. These cells secrete abundant serine proteases as well as chemical mediators and cytokines; however, the expression profiles and functions of their endogenous inhibitors remain elusive. We found that murine secretory leukoprotease inhibitor (SLPI) is expressed in basophils and eosinophils but in not in mast cells. SLPI-deficient () basophils produce more cytokines than wild-type mice after IgE stimulation. Although the deletion of SLPI in basophils did not affect the release of chemical mediators upon IgE stimulation, the enzymatic activity of the serine protease tryptase was increased in basophils. Mice transferred with basophils were highly sensitive to IgE-mediated chronic allergic inflammation. Eosinophils lacking SLPI showed greater interleukin-6 secretion and invasive activity upon lipopolysaccharide stimulation, and the expression of matrix metalloproteinase-9 by these eosinophils was increased without stimulation. The absence of SLPI increases JNK1 phosphorylation at the steady state, and augments the serine phosphorylation of JNK1-downstream ETS transcriptional factor Elk-1 in eosinophils upon stimulation. Of note, SLPI interacts with a scaffold protein, JNK-interacting protein 3 (JIP3), that constitutively binds to the cytoplasmic domain of toll-like receptor (TLR) 4, suggesting that SLPI controls Elk-1 activation binding to JIP3 in eosinophils. Mice transferred with eosinophils showed the exacerbation of chitin-induced allergic inflammation. These findings showed that SLPI is a negative regulator in allergic effector cells and suggested a novel inhibitory role of SLPI in the TLR4 signaling pathways.
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http://dx.doi.org/10.3389/fimmu.2017.01538DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5693852PMC
November 2017

PirB regulates asymmetries in hippocampal circuitry.

PLoS One 2017 8;12(6):e0179377. Epub 2017 Jun 8.

Department of Biology, Faculty of Science, Kyushu University, Fukuoka, Japan.

Left-right asymmetry is a fundamental feature of higher-order brain structure; however, the molecular basis of brain asymmetry remains unclear. We recently identified structural and functional asymmetries in mouse hippocampal circuitry that result from the asymmetrical distribution of two distinct populations of pyramidal cell synapses that differ in the density of the NMDA receptor subunit GluRε2 (also known as NR2B, GRIN2B or GluN2B). By examining the synaptic distribution of ε2 subunits, we previously found that β2-microglobulin-deficient mice, which lack cell surface expression of the vast majority of major histocompatibility complex class I (MHCI) proteins, do not exhibit circuit asymmetry. In the present study, we conducted electrophysiological and anatomical analyses on the hippocampal circuitry of mice with a knockout of the paired immunoglobulin-like receptor B (PirB), an MHCI receptor. As in β2-microglobulin-deficient mice, the PirB-deficient hippocampus lacked circuit asymmetries. This finding that MHCI loss-of-function mice and PirB knockout mice have identical phenotypes suggests that MHCI signals that produce hippocampal asymmetries are transduced through PirB. Our results provide evidence for a critical role of the MHCI/PirB signaling system in the generation of asymmetries in hippocampal circuitry.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0179377PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5464656PMC
September 2017

Quantitative trait loci for large sink capacity enhance rice grain yield under free-air CO enrichment conditions.

Sci Rep 2017 05 12;7(1):1827. Epub 2017 May 12.

NARO Institute of Crop Science, 2-1-2 Kannondai, Tsukuba, Ibaraki, 305-8602, Japan.

The global atmospheric CO concentration has been increasing annually. To determine the trait that effectively increases rice (Oryza sativa L.) grain yield under increased atmospheric CO concentrations, as predicted in the near future, we grew a chromosome segment substitution line (CSSL) and a near-isogenic line (NIL) producing high spikelet numbers per panicle (CSSL-GN1 and NIL-APO1, respectively) under free-air CO enrichment (FACE) conditions and examined the effects of a large sink capacity on grain yield, its components, and growth-related traits under increased atmospheric CO concentrations. Under ambient conditions, CSSL-GN1 and NIL-APO1 exhibited a similar grain yield to Koshihikari, as a result of the trade-off between increased spikelet number and reduced grain filling. However, under FACE conditions, CSSL-GN1 and NIL-APO1 had an equal or a higher grain yield than Koshihikari because of the higher number of spikelets and lower reduction in grain filling. Thus, the improvement of source activity by increased atmospheric CO concentrations can lead to enhanced grain yield in rice lines that have a large sink capacity. Therefore, introducing alleles that increase sink capacity into conventional varieties represents a strategy that can be used to develop high-yielding varieties under increased atmospheric CO concentrations, such as those predicted in the near future.
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http://dx.doi.org/10.1038/s41598-017-01690-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5431863PMC
May 2017

EXPLORING OF IMMUNE INHIBITORY RECEPTORS THAT CHARACTERIZE PATHOGENIC PLASMA CELLS IN SYSTEMIC LUPUS ERYTHEMATOSUS.

Arerugi 2017 ;66(1):27-31

Department of Experimental Immunology, Institute of Development, Aging and Cancer, Tohoku University.

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http://dx.doi.org/10.15036/arerugi.66.27DOI Listing
May 2017

Advax, a Delta Inulin Microparticle, Potentiates In-built Adjuvant Property of Co-administered Vaccines.

EBioMedicine 2017 Feb 1;15:127-136. Epub 2016 Dec 1.

Laboratory of Adjuvant Innovation, National Institutes of Biomedical Innovation, Health and Nutrition, Osaka 567-0085, Japan; Laboratory of Vaccine Science, WPI Immunology Frontier Research Centre, Osaka University, Osaka 565-0871, Japan. Electronic address:

Advax, a delta inulin-derived microparticle, has been developed as an adjuvant for several vaccines. However, its immunological characteristics and potential mechanism of action are yet to be elucidated. Here, we show that Advax behaves as a type-2 adjuvant when combined with influenza split vaccine, a T helper (Th)2-type antigen, but behaves as a type-1 adjuvant when combined with influenza inactivated whole virion (WV), a Th1-type antigen. In addition, an adjuvant effect was not observed when Advax-adjuvanted WV vaccine was used to immunize toll-like receptor (TLR) 7 knockout mice which are unable to respond to RNA contained in WV antigen. Similarly, no adjuvant effect was seen when Advax was combined with endotoxin-free ovalbumin, a neutral Th0-type antigen. An adjuvant effect was also not seen in tumor necrosis factor (TNF)-α knockout mice, and the adjuvant effect required the presences of dendritic cells (DCs) and phagocytic macrophages. Therefore, unlike other adjuvants, Advax potentiates the intrinsic or in-built adjuvant property of co-administered antigens. Hence, Advax is a unique class of adjuvant which can potentiate the intrinsic adjuvant feature of the vaccine antigens through a yet to be determined mechanism.
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http://dx.doi.org/10.1016/j.ebiom.2016.11.015DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5233800PMC
February 2017

TREM2/DAP12 Signal Elicits Proinflammatory Response in Microglia and Exacerbates Neuropathic Pain.

J Neurosci 2016 10;36(43):11138-11150

Department of Functional Anatomy and Neuroscience, Nagoya University Graduate School of Medicine, Nagoya 466-8550, Japan,

Neuropathic pain afflicts millions of people, and the development of an effective treatment for this intractable pain is an urgent issue. Recent evidence has implicated microglia in neuropathic pain. The present study showed that the DNAX-activating protein of 12 kDa (DAP12) and its associated "triggering receptor expressed on myeloid cells 2" (TREM2) were predominantly expressed by microglia in the dorsal horn after spinal nerve injury, revealing a role for TREM2/DAP12 signaling in neuropathic pain. Nerve injury-induced proinflammatory cytokine expression in microglia and pain behaviors were significantly suppressed in Dap12-deficient mice. Furthermore, intrathecal administration of TREM2 agonistic antibody induced proinflammatory cytokine expression, as well as neuropathic pain, in mice without nerve injury. The agonistic antibody induced proinflammatory responses and neuropathic pain was not observed in Dap12-deficient mice. Together, these results suggest that TREM2/DAP12-mediated signals in microglia exacerbate nerve injury-induced neuropathic pain by inducing proinflammatory cytokine secretion from microglia. Suppression of DAP12-mediated signals could be a therapeutic target for neuropathic pain.

Significance Statement: Recent studies have revealed that activated microglia in the spinal dorsal horn exacerbate neuropathic pain, which has suggested that suppression of microglial activity should be considered as a therapeutic target. However, only a few molecules have been identified as regulators of microglial activity. In this study, we focused on a receptor complex of TREM2 and DAP12, both of which are expressed by microglia and have been implicated in the pathogenesis of Alzheimer's disease, and demonstrated that TREM2/DAP12 signaling promoted proinflammatory responses in microglia and exacerbates neuropathic pain. The present results revealed the functional significance of TREM2/DAP12 signaling in microglial activation after neuronal injury, and could help in the development of treatments for neuropathic pain and neurodegenerative diseases.
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http://dx.doi.org/10.1523/JNEUROSCI.1238-16.2016DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6705657PMC
October 2016

Tolerogenic immunoreceptor ILT3/LILRB4 paradoxically marks pathogenic auto-antibody-producing plasmablasts and plasma cells in non-treated SLE.

Int Immunol 2016 12 14;28(12):597-604. Epub 2016 Oct 14.

Department of Experimental Immunology, Institute of Development, Aging and Cancer, Tohoku University, 4-1 Seiryo, Sendai 980-8575, Japan

Plasmablasts and plasma cells (PBs and PCs) producing pathogenic auto-antibodies in patients with systemic autoimmune diseases could be a better target for specific therapies for the disease than general immunosuppression or pan- or activated B-cell targeting. Our previous study indicated that leukocyte immunoglobulin-like receptor (LILR) B4 (B4, also known as ILT3/LIR-5/CD85k), a tolerogenic receptor in antigen-presenting cells, is ectopically expressed on the PB/PC surface in healthy individuals. Here, we show that the enlarged population size of PBs/PCs with augmented B4 expression is characteristic in non-treated systemic lupus erythematosus (SLE). Paradoxically, the transcription frequency of the anti-double-strand DNA immunoglobulin-coding V sequence in the B4 population of non-treated SLE was significantly higher than that in B4 cells. B4 and B4 PBs/PCs were suggested to be developmentally equivalent based on the simultaneous generation of these populations upon activation of memory B cells in vitro B4 expression was found to be induced efficiently by IL-2, while IFN-α effectively induced B4 PBs/PCs in vitro Utilizing the elevated B4 will support opening a new avenue for identifying the mechanism for generation of, and additional molecular markers for, pathogenic cells.
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http://dx.doi.org/10.1093/intimm/dxw044DOI Listing
December 2016

A Histone Methyltransferase ESET Is Critical for T Cell Development.

J Immunol 2016 09 10;197(6):2269-79. Epub 2016 Aug 10.

Department of Immunology and Pathology, Research Center for Hepatitis and Immunology, Research Institute, National Center for Global Health and Medicine, Chiba 272-8516, Japan;

ESET/SETDB1, one of the major histone methyltransferases, catalyzes histone 3 lysine 9 (H3K9) trimethylation. ESET is critical for suppressing expression of retroviral elements in embryonic stem cells; however, its role in the immune system is not known. We found that thymocyte-specific deletion of ESET caused impaired T cell development, with CD8 lineage cells being most severely affected. Increased apoptosis of CD8 single-positive cells was observed, and TCR-induced ERK activation was severely inhibited in ESET(-/-) thymocytes. Genome-wide comprehensive analysis of mRNA expression and H3K9 trimethylation revealed that ESET regulates expression of numerous genes in thymocytes. Among them, FcγRIIB, whose signaling can inhibit ERK activation, was strongly and ectopically expressed in ESET(-/-) thymocytes. Indeed, genetic depletion of FcγRIIB in ESET(-/-) thymocytes rescued impaired ERK activation and partially restored defective positive selection in ESET(-/-) mice. Therefore, impaired T cell development in ESET(-/-) mice is partly due to the aberrant expression of FcγRIIB. Collectively, to our knowledge, we identify ESET as the first trimethylated H3K9 histone methyltransferase playing a crucial role in T cell development.
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http://dx.doi.org/10.4049/jimmunol.1502486DOI Listing
September 2016

Precise estimation of genomic regions controlling lodging resistance using a set of reciprocal chromosome segment substitution lines in rice.

Sci Rep 2016 07 28;6:30572. Epub 2016 Jul 28.

Institute of Agriculture, Graduate School, Tokyo University of Agriculture and Technology, Fuchu, Tokyo 183-8509, Japan.

Severe lodging has occurred in many improved rice varieties after the recent strong typhoons in East and Southeast Asian countries. The indica variety Takanari possesses strong culm characteristics due to its large section modulus, which indicates culm thickness, whereas the japonica variety Koshihikari is subject to substantial bending stress due to its thick cortical fibre tissue. To detect quantitative trait loci (QTLs) for lodging resistance and to eliminate the effects of genetic background, we used reciprocal chromosome segment substitution lines (CSSLs) derived from a cross between Koshihikari and Takanari. The oppositional effects of QTLs for section modulus were confirmed in both genetic backgrounds on chromosomes 1, 5 and 6, suggesting that these QTLs are not affected by the genetic background and are controlled independently by a single factor. The candidate region of a QTL for section modulus included SD1. The section modulus of NIL-sd1 was lower than that of Koshihikari, whereas the section modulus of NIL-SD1 was higher than that of Takanari. This result indicated that those regions regulate the culm thickness. The reciprocal effects of the QTLs for cortical fibre tissue thickness were confirmed in both genetic backgrounds on chromosome 9 using CSSLs.
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http://dx.doi.org/10.1038/srep30572DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4964586PMC
July 2016

Mice Deficient in Angiopoietin-like Protein 2 (Angptl2) Gene Show Increased Susceptibility to Bacterial Infection Due to Attenuated Macrophage Activity.

J Biol Chem 2016 09 11;291(36):18843-52. Epub 2016 Jul 11.

From the Departments of Molecular Genetics, Core Research for Evolutional Science and Technology (CREST), Japan Agency for Medical Research and Development (AMED), Tokyo 102-0076, Japan

Macrophages play crucial roles in combatting infectious disease by promoting inflammation and phagocytosis. Angiopoietin-like protein 2 (ANGPTL2) is a secreted factor that induces tissue inflammation by attracting and activating macrophages to produce inflammatory cytokines in chronic inflammation-associated diseases such as obesity-associated metabolic syndrome, atherosclerosis, and rheumatoid arthritis. Here, we asked whether and how ANGPTL2 activates macrophages in the innate immune response. ANGPTL2 was predominantly expressed in proinflammatory mouse bone marrow-derived differentiated macrophages (GM-BMMs) following GM-CSF treatment relative to anti-inflammatory cells (M-BMMs) established by M-CSF treatment. Expression of the proinflammatory markers IL-1β, IL-12p35, and IL-12p40 significantly decreased in GM-BMMs from Angptl2-deficient compared with wild-type (WT) mice, suggestive of attenuated proinflammatory activity. We also report that ANGPTL2 inflammatory signaling is transduced through integrin α5β1 rather than through paired immunoglobulin-like receptor B. Interestingly, Angptl2-deficient mice were more susceptible to infection with Salmonella enterica serovar Typhimurium than were WT mice. Moreover, nitric oxide (NO) production by Angptl2-deficient GM-BMMs was significantly lower than in WT GM-BMMs. Collectively, our findings suggest that macrophage-derived ANGPTL2 promotes an innate immune response in those cells by enhancing proinflammatory activity and NO production required to fight infection.
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http://dx.doi.org/10.1074/jbc.M116.720870DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5009257PMC
September 2016

TLR signals posttranscriptionally regulate the cytokine trafficking mediator sortilin.

Sci Rep 2016 05 25;6:26566. Epub 2016 May 25.

Department of Immunology, Kanazawa Medical University, Kahoku Uchinada, Ishikawa, 920-0293, JAPAN.

Regulating the transcription, translation and secretion of cytokines is crucial for controlling the appropriate balance of inflammation. Here we report that the sorting receptor sortilin plays a key role in cytokine production. We observed interactions of sortilin with multiple cytokines including IFN-α, and sortilin depletion in plasmacytoid dendritic cells (pDCs) led to a reduction of IFN-α secretion, suggesting a pivotal role of sortilin in the exocytic trafficking of IFN-α in pDCs. Moreover, sortilin mRNA was degraded posttranscriptionally upon stimulation with various TLR ligands. Poly-rC-binding protein 1 (PCBP1) recognized the C-rich element (CRE) in the 3' UTR of sortilin mRNA, and depletion of PCBP1 enhanced the degradation of sortilin transcripts, suggesting that PCBP1 can act as a trans-acting factor to stabilize sortilin transcripts. The nucleotide-binding ability of PCBP1 was impaired by zinc ions and alterations of intracellular zinc affect sortilin expression. PCBP1 may therefore control the stability of sortilin transcripts by sensing intracellular zinc levels. Collectively, our findings provide insights into the posttranslational regulation of cytokine production through the posttranscriptional control of sortilin expression by TLR signals.
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http://dx.doi.org/10.1038/srep26566DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4879639PMC
May 2016

The immunosuppressive effect of domain-deleted dimer of HLA-G2 isoform in collagen-induced arthritis mice.

Hum Immunol 2016 Sep 21;77(9):754-9. Epub 2016 Jan 21.

Laboratory of Biomolecular Science, Faculty of Pharmaceutical Sciences, Hokkaido University, Sapporo, Japan; Center for Research and Education on Drug Discovery, Faculty of Pharmaceutical Sciences, Hokkaido University, Sapporo, Japan. Electronic address:

HLA-G is involved in maternal-fetal immune tolerance and is reported to be a natural tolerogenic molecule. Seven-spliced isoforms including dimeric and β2m-free forms have been identified. The major isoform, HLA-G1 (and its soluble type HLA-G5), binds to the inhibitory immune receptors, leukocyte immunoglobulin (Ig)-like receptor (LILR) B1 and LILRB2. We previously reported that HLA-G1 also binds to paired Ig-like receptor (PIR)-B, a mouse homolog of LILRBs, and had a significant immunosuppressive effect in collagen-induced arthritis (CIA) mice. Although HLA-G2 and its soluble form HLA-G6 bind specifically to LILRB2, its functional characteristics are largely unknown. In this study, we report the significant immunosuppressive effect of HLA-G2 dimer in CIA mice. Surface plasmon resonance analysis revealed a specific interaction of HLA-G2 with PIR-B. CIA mice were administered HLA-G2 protein subcutaneously once in the left footpad and clinical severity was evaluated in a double-blind study. A single administration of HLA-G2 maintained a suppressive effect for over 1month. These results suggested that the HLA-G2 protein might be a useful biopharmaceutical for the treatment of rheumatoid arthritis by binding to inhibitory PIR-B.
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http://dx.doi.org/10.1016/j.humimm.2016.01.010DOI Listing
September 2016

Impaired Fracture Healing Caused by Deficiency of the Immunoreceptor Adaptor Protein DAP12.

PLoS One 2015 1;10(6):e0128210. Epub 2015 Jun 1.

Department of Orthopaedic Surgery, Tohoku University Graduate School of Medicine 1-1 Seiryo-machi, Aobaku, Sendai, Miyagi, Japan.

Osteoclasts play an important role in bone metabolism, but their exact role in fracture healing remains unclear. DAP12 is an immunoadaptor protein with associated immunoreceptors on myeloid lineage cells, including osteoclasts. Its deficiency causes osteopetrosis due to suppression of osteoclast development and activation. In this report, we assessed the impact of DAP12 on the fracture healing process using C57BL/6 (B6) and DAP12-/- mice. Healing was evaluated using radiography, micro-CT, histology, immunohistochemistry and real-time RT-PCR. Radiography showed lower callus volume and lower callus radiolucency in DAP12-/- mice during later stages. Micro-CT images and quantitative structural analysis indicated that DAP12-/- mice developed calluses of dense trabecular structures and experienced deteriorated cortical shell formation on the surface. Histologically, DAP12-/- mice showed less cartilaginous resorption and woven bone formation. In addition, prominent cortical shell formation was much less in DAP12-/- mice. Immunohistochemistry revealed lower invasion of F4/80 positive monocytes and macrophages into the fracture hematoma in DAP12-/- mice. The expression levels of Col1a1, Col2a1 and Col10a1 in DAP12-/- mice increased and subsequently became higher than those in B6 mice. There was a decrease in the gene expression of Tnf during the early stages in DAP12-/- mice. Our results indicate that DAP12 deficiency impairs fracture healing, suggesting a significant role of DAP12 in the initial inflammatory response, bone remodeling and regeneration.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0128210PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4452492PMC
April 2016

Genetic architecture of variation in heading date among Asian rice accessions.

BMC Plant Biol 2015 May 8;15:115. Epub 2015 May 8.

National Institute of Agrobiological Sciences, 2-1-2 Kannondai, 305-8602, Tsukuba, Ibaraki, Japan.

Background: Heading date, a crucial factor determining regional and seasonal adaptation in rice (Oryza sativa L.), has been a major selection target in breeding programs. Although considerable progress has been made in our understanding of the molecular regulation of heading date in rice during last two decades, the previously isolated genes and identified quantitative trait loci (QTLs) cannot fully explain the natural variation for heading date in diverse rice accessions.

Results: To genetically dissect naturally occurring variation in rice heading date, we collected QTLs in advanced-backcross populations derived from multiple crosses of the japonica rice accession Koshihikari (as a common parental line) with 11 diverse rice accessions (5 indica, 3 aus, and 3 japonica) that originate from various regions of Asia. QTL analyses of over 14,000 backcrossed individuals revealed 255 QTLs distributed widely across the rice genome. Among the detected QTLs, 128 QTLs corresponded to genomic positions of heading date genes identified by previous studies, such as Hd1, Hd6, Hd3a, Ghd7, DTH8, and RFT1. The other 127 QTLs were detected in different chromosomal regions than heading date genes.

Conclusions: Our results indicate that advanced-backcross progeny allowed us to detect and confirm QTLs with relatively small additive effects, and the natural variation in rice heading date could result from combinations of large- and small-effect QTLs. We also found differences in the genetic architecture of heading date (flowering time) among maize, Arabidopsis, and rice.
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http://dx.doi.org/10.1186/s12870-015-0501-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4424449PMC
May 2015

Endoplasmic Protein Nogo-B (RTN4-B) Interacts with GRAMD4 and Regulates TLR9-Mediated Innate Immune Responses.

J Immunol 2015 Jun 27;194(11):5426-36. Epub 2015 Apr 27.

Department of Experimental Immunology, Institute of Development, Aging and Cancer, Tohoku University, Sendai 980-8575, Japan; and

TLRs are distributed in their characteristic cellular or subcellular compartments to efficiently recognize specific ligands and to initiate intracellular signaling. Whereas TLRs recognizing pathogen-associated lipids or proteins are localized to the cell surface, nucleic acid-sensing TLRs are expressed in endosomes and lysosomes. Several endoplasmic reticulum (ER)-resident proteins are known to regulate the trafficking of TLRs to the specific cellular compartments, thus playing important roles in the initiation of innate immune responses. In this study, we show that an ER-resident protein, Nogo-B (or RTN4-B), is necessary for immune responses triggered by nucleic acid-sensing TLRs, and that a newly identified Nogo-B-binding protein (glucosyltransferases, Rab-like GTPase activators and myotubularins [GRAM] domain containing 4 [GRAMD4]) negatively regulates the responses. Production of inflammatory cytokines in vitro by macrophages stimulated with CpG-B oligonucleotides or polyinosinic:polycytidylic acid was attenuated in the absence of Nogo-B, which was also confirmed in serum samples from Nogo-deficient mice injected with polyinosinic:polycytidylic acid. Although a deficiency of Nogo-B did not change the incorporation or delivery of CpG to endosomes, the localization of TLR9 to endolysosomes was found to be impaired. We identified GRAMD4 as a downmodulator for TLR9 response with a Nogo-B binding ability in ER, because our knockdown and overexpression experiments indicated that GRAMD4 suppresses the TLR9 response and knockdown of Gramd4 strongly enhanced the response in the absence of Nogo-B. Our findings indicate a critical role of Nogo-B and GRAMD4 in trafficking of TLR9.
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http://dx.doi.org/10.4049/jimmunol.1402006DOI Listing
June 2015

Platelets convert peripheral blood circulating monocytes to regulatory cells via immunoglobulin G and activating-type Fcγ receptors.

BMC Immunol 2015 Apr 21;16:20. Epub 2015 Apr 21.

Department of Experimental Immunology, Institute of Development, Aging and Cancer, Tohoku University, 4-1 Seiryo-machi, Aoba-ku, Sendai, 980-8575, Japan.

Background: Monocytes and macrophages produce interleukin (IL)-10, an immunoregulatory cytokine and a potent therapeutic tool for immune disorders. Augmentation of IL-10 production with a concomitant reduction of proinflammatory cytokines in macrophages in vitro is attained by doubly stimulating the cells with a toll-like receptor ligand and immunoglobulin (Ig)G immune complexes, a response known as that of regulatory (or alternatively activated/M2) macrophages. However, it has not been explored sufficiently how such a regulatory response could be exploited for anti-inflammation. Our objective is to find a potential way or condition for augmenting IL-10 by monocytes/macrophages in vivo and in vitro.

Results: We show that platelets, when they are opsonized with IgG, can convert human peripheral blood circulating monocytes to IL-10-producing regulatory monocytes in vitro and also in a murine in vivo model. Co-culturing of platelets and monocytes in the presence of anti-integrin IgG and a bacterial lipopolysaccharide augmented IL-10 production via a direct interaction between platelets and monocytes. This novel way of enhancing IL-10 was mediated by activating-type Fc receptors for IgG.

Conclusion: These findings indicate that the IgG-bound platelet-induced conversion of monocytes to regulatory cells might provide a novel strategy for controlling inflammation.
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http://dx.doi.org/10.1186/s12865-015-0086-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4407389PMC
April 2015