Shizuo Akira

Bio: Shizuo Akira is an academic researcher from Osaka University. The author has contributed to research in topics: Innate immune system & Immune system. The author has an hindex of 261, co-authored 1308 publications receiving 320561 citations. Previous affiliations of Shizuo Akira include University of California, Berkeley & Wakayama Medical University.

CD44 participates in IP-10 induction in cells in which hepatitis C virus RNA is replicating, through an interaction with Toll-like receptor 2 and hyaluronan.

Abstract: The mechanisms of induction of liver injury during chronic infection with hepatitis C virus (HCV) are not well understood. Gamma interferon (IFN-γ)-inducible protein 10 (IP-10), a member of the CXC chemokine family, is expressed in the liver of chronic hepatitis C (CHC) patients and selectively recruits activated T cells to the sites of inflammation. Recently, it was shown that a low plasma concentration of IP-10 in CHC patients was closely associated with the outcome of antiviral therapy. In this study, we examined the role of the Toll-like receptor (TLR) pathway on IP-10 production in cells replicating HCV. Among the CXC chemokines, the expression of IP-10 was specifically increased in cells replicating HCV upon stimulation with conventional TLR2 ligands. The enhancement of IP-10 production upon stimulation with TLR2 ligands in cells replicating HCV induced CD44 expression. CD44 is a broadly distributed type I transmembrane glycoprotein and a receptor for the glycosaminoglycan hyaluronan (HA). In CHC patients, the expression of HA in serum has been shown to increase in accord with the progression of liver fibrosis, and HA also works as a ligand for TLR2. In the present study, IP-10 production upon HA stimulation was dependent on the expression of TLR2 and CD44, and a direct association between TLR2 and CD44 was observed. These results suggest that endogenous expression of HA in hepatocytes in CHC patients participates in IP-10 production through an engagement of TLR2 and CD44.

Microsomal prostaglandin E synthase-1 contributes to ischaemic excitotoxicity through prostaglandin E2 EP3 receptors

Abstract: Background and purpose: Although microsomal prostaglandin E synthase (mPGES)-1 is known to contribute to stroke injury, the underlying mechanisms remain poorly understood. This study examines the hypothesis that EP3 receptors contribute to stroke injury as downstream effectors of mPGES-1 neurotoxicity through Rho kinase activation. Experimental approach: We used a glutamate-induced excitotoxicity model in cultured rat and mouse hippocampal slices and a mouse middle cerebral artery occlusion–reperfusion model. Effects of an EP3 receptor antagonist on neuronal damage in mPGES-1 knockout (KO) mice was compared with that in wild-type (WT) mice. Key results: In cultures of rat hippocampal slices, the mRNAs of EP1–4 receptors were constitutively expressed and only the EP3 receptor antagonist ONO-AE3-240 attenuated and only the EP3 receptor agonist ONO-AE-248 augmented glutamate-induced excitotoxicity in CA1 neurons. Hippocampal slices from mPGES-1 KO mice showed less excitotoxicity than those from WT mice and the EP3 receptor antagonist did not attenuate the excitotoxicity. In transient focal ischaemia models, injection (i.p.) of an EP3 antagonist reduced infarction, oedema and neurological dysfunction in WT mice, but not in mPGES-1 KO mice, which showed less injury than WT mice. EP3 receptor agonist-induced augmentation of excitotoxicity in vitro was ameliorated by the Rho kinase inhibitor Y-27632 and Pertussis toxin. The Rho kinase inhibitor HA-1077 also ameliorated stroke injury in vivo. Conclusion and implications: Activity of mPGES-1 exacerbated stroke injury through EP3 receptors and activation of Rho kinase and/or Gi. Thus, mPGES-1 and EP3 receptors may be valuable therapeutic targets for treatment of human stroke. This article is commented on by Andreasson, pp. 844–846 of this issue. To view this commentary visit http://dx.doi.org/10.1111/j.1476-5381.2010.00715.x

Regulation of Id2 expression by CCAAT/enhancer binding protein β

Abstract: Mice deficient for Id2, a negative regulator of basic helix-loop-helix (bHLH) transcription factors, exhibit a defect in lactation due to impaired lobuloalveolar development during pregnancy, similar to the mice lacking the CCAAT enhancer binding protein (C/EBP) beta. Here, we show that Id2 is a direct target of C/EBPbeta. Translocation of C/EBPbeta into the nucleus, which was achieved by using a system utilizing the fusion protein between C/EBPbeta and the ligand-binding domain of the human estrogen receptor (C/EBPbeta-ERT), demonstrated the rapid induction of endogenous Id2 expression. In reporter assays, transactivation of the Id2 promoter by C/EBPbeta was observed and, among three potential C/EBPbeta binding sites found in the 2.3 kb Id2 promoter region, the most proximal element was responsible for the transactivation. Electrophoretic mobility shift assay (EMSA) identified this element as a core sequence to which C/EBPbeta binds. Chromatin immunoprecipitation (ChIP) furthermore confirmed the presence of C/EBPbeta in the Id2 promoter region. Northern blotting showed that Id2 expression in C/EBPbeta-deficient mammary glands was reduced at 10 days post coitus (d.p.c.), compared with that in wild-type mammary glands. Thus, our data demonstrate that Id2 is a direct target of C/EBPbeta and provide insight into molecular mechanisms underlying mammary gland development during pregnancy.

NFATc1 mediates Toll-like receptor-independent innate immune responses during Trypanosoma cruzi infection.

Abstract: Host defense against the intracellular protozoan parasite Trypanosoma cruzi depends on Toll-like receptor (TLR)-dependent innate immune responses. Recent studies also suggest the presence of TLR-independent responses to several microorganisms, such as viruses, bacteria, and fungi. However, the TLR-independent responses to protozoa remain unclear. Here, we demonstrate a novel TLR-independent innate response pathway to T. cruzi. Myd88−/−Trif−/− mice lacking TLR signaling showed normal T. cruzi-induced Th1 responses and maturation of dendritic cells (DCs), despite high sensitivity to the infection. IFN-γ was normally induced in T. cruzi-infected Myd88−/−Trif−/− innate immune cells, and further was responsible for the TLR-independent Th1 responses and DC maturation after T. cruzi infection. T. cruzi infection induced elevation of the intracellular Ca2+ level. Furthermore, T. cruzi-induced IFN-γ expression was blocked by inhibition of Ca2+ signaling. NFATc1, which plays a pivotal role in Ca2+ signaling in lymphocytes, was activated in T. cruzi-infected Myd88−/−Trif−/− innate immune cells. T. cruzi-infected Nfatc1−/− fetal liver DCs were impaired in IFN-γ production and DC maturation. These results demonstrate that NFATc1 mediates TLR-independent innate immune responses in T. cruzi infection.

疟原虫var基因转换速率变化导致抗原变异[英]／Paul H, Robert P, Christodoulou Z, et al//Proc Natl Acad Sci U S A

Abstract: 抗原变异可使得多种致病微生物易于逃避宿主免疫应答。表达在感染红细胞表面的恶性疟原虫红细胞表面蛋白1（PfPMP1）与感染红细胞、内皮细胞、树突状细胞以及胎盘的单个或多个受体作用，在黏附及免疫逃避中起关键的作用。每个单倍体基因组var基因家族编码约60种成员，通过启动转录不同的var基因变异体为抗原变异提供了分子基础。

Safety and Efficacy of the BNT162b2 mRNA Covid-19 Vaccine.

Abstract: Background Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and the resulting coronavirus disease 2019 (Covid-19) have afflicted tens of millions of people in a world...

Cancer-related inflammation.

Abstract: The mediators and cellular effectors of inflammation are important constituents of the local environment of tumours. In some types of cancer, inflammatory conditions are present before a malignant change occurs. Conversely, in other types of cancer, an oncogenic change induces an inflammatory microenvironment that promotes the development of tumours. Regardless of its origin, 'smouldering' inflammation in the tumour microenvironment has many tumour-promoting effects. It aids in the proliferation and survival of malignant cells, promotes angiogenesis and metastasis, subverts adaptive immune responses, and alters responses to hormones and chemotherapeutic agents. The molecular pathways of this cancer-related inflammation are now being unravelled, resulting in the identification of new target molecules that could lead to improved diagnosis and treatment.