Heung Kyu Lee

Korea Advanced Institute of Science and Technology

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Ji Eun Oh

Jaseng Hospital of Korean Medicine

Akiko Iwasaki

Howard Hughes Medical Institute

Hi Eun Jung

Korea Advanced Institute of Science and Technology

Inhwa Hwang

Yonsei University

Je‐Wook Yu

Yonsei University

Wei Cao

The University of Texas Health Science Center at Houston

Robert W. Williams

University of Tennessee Health Science Center

Chul‐Ho Lee

Korea Research Institute of Bioscience and Biotechnology

Duck Jong Han

Asan Medical Center

Seulgi Kang

Korea University of Science and Technology

Cooperative Institutions

Yonsei University

Korea Advanced Institute of Science and Technology

Chungnam National University

University of Ulsan

Korea Research Institute of Bioscience and Biotechnology

Asan Medical Center

Sungkyunkwan University

Catholic University of Korea

Yale University

Korea Institute of Science and Technology

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Autophagy-Dependent Viral Recognition by Plasmacytoid Dendritic Cells

Science (2007)

Heung Kyu Lee Jennifer M. Lund Balaji Ramanathan Noboru Mizushima Akiko Iwasaki

Plasmacytoid dendritic cells (pDCs) detect viruses in the acidified endosomes by means of Toll-like receptors (TLRs). Yet, pDC responses to certain single-stranded RNA (ssRNA) viruses occur only after live viral infection. We present evidence here that the recognition of such viruses by TLR7 requires transport of cytosolic viral replication intermediates into the lysosome by the process of autophagy. In addition, autophagy was found to be required for the production of interferon-α by pDCs. These results support a key role for autophagy in mediating ssRNA virus detection and interferon-α secretion by pDCs and suggest that cytosolic replication intermediates of viruses serve as pathogen signatures recognized by TLR7.

TLR7

Plasmacytoid dendritic cell

Picornavirus

10.1126/science.1136880

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Citations (832)

Vibrio vulnificus quorum-sensing molecule cyclo(Phe-Pro) inhibits RIG-I-mediated antiviral innate immunity

Nature Communications (2018)

Wooseong Lee Seung‐Hoon Lee Minwoo Kim Jae-Su Moon Geon‐Woo Kim

Abstract The recognition of pathogen-derived ligands by pattern recognition receptors activates the innate immune response, but the potential interaction of quorum-sensing (QS) signaling molecules with host anti-viral defenses remains largely unknown. Here we show that the Vibrio vulnificus QS molecule cyclo(Phe-Pro) (cFP) inhibits interferon (IFN)-β production by interfering with retinoic-acid-inducible gene-I (RIG-I) activation. Binding of cFP to the RIG-I 2CARD domain induces a conformational change in RIG-I, preventing the TRIM25-mediated ubiquitination to abrogate IFN production. cFP enhances susceptibility to hepatitis C virus (HCV), as well as Sendai and influenza viruses, each known to be sensed by RIG-I but did not affect the melanoma-differentiation-associated gene 5 (MDA5)-recognition of norovirus. Our results reveal an inter-kingdom network between bacteria, viruses and host that dysregulates host innate responses via a microbial quorum-sensing molecule modulating the response to viral infection.

MDA5

RIG-I

Pathogen-associated molecular pattern

Vibrio vulnificus

Sendai virus

10.1038/s41467-018-04075-1

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Citations (40)

Immunosuppressive effects of tautomycetinin vivoandin vitrovia T cell-specific apoptosis induction

Proceedings of the National Academy of Sciences (2002)

Jae‐Hyuck Shim Heung Kyu Lee Eun-Ju Chang Wook‐Jin Chae Jin-Hwan Han

Tautomycetin (TMC) was identified as an immunosuppressor of activated T cells. Inhibition of T cell proliferation with TMC was observed at concentrations 100-fold lower than those needed to achieve maximal inhibition with cyclosporin A (CsA). TMC specifically blocked tyrosine phosphorylation of intracellular signal mediators downstream of Src tyrosine kinases in a T cell-specific manner, leading to apoptosis due to cleavage of Bcl-2, caspase-9, caspase-3, and poly(ADP-ribose) polymerase, but not caspase-1. In TMC-treated rats that received a heterotopic cardiac allograft, the graft survived more than 160 days, comparable to graft survival in allografted rats treated with CsA. Thus, TMC, whose mechanism of action is different from that of CsA or FK506, can be used as a potent T cell-specific immunosuppressor.

Cleavage (geology)

10.1073/pnas.162522099

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Citations (54)

Reduced oxidative capacity in macrophages results in systemic insulin resistance

Nature Communications (2018)

Saet-Byel Jung Min Jeong Choi Dongryeol Ryu Hyon‐Seung Yi Seong Eun Lee

Oxidative functions of adipose tissue macrophages control the polarization of M1-like and M2-like phenotypes, but whether reduced macrophage oxidative function causes systemic insulin resistance in vivo is not clear. Here, we show that mice with reduced mitochondrial oxidative phosphorylation (OxPhos) due to myeloid-specific deletion of CR6-interacting factor 1 (Crif1), an essential mitoribosomal factor involved in biogenesis of OxPhos subunits, have M1-like polarization of macrophages and systemic insulin resistance with adipose inflammation. Macrophage GDF15 expression is reduced in mice with impaired oxidative function, but induced upon stimulation with rosiglitazone and IL-4. GDF15 upregulates the oxidative function of macrophages, leading to M2-like polarization, and reverses insulin resistance in ob/ob mice and HFD-fed mice with myeloid-specific deletion of Crif1. Thus, reduced macrophage oxidative function controls systemic insulin resistance and adipose inflammation, which can be reversed with GDF15 and leads to improved oxidative function of macrophages.

Macrophage polarization

10.1038/s41467-018-03998-z

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A mechanism for the induction of type 2 immune responses by a protease allergen in the genital tract

Proceedings of the National Academy of Sciences (2017)

Ji Eun Oh Dong Sun Oh Hi Eun Jung Heung Kyu Lee

The genital mucosa is a barrier that is constantly exposed to a variety of pathogens, allergens, and external stimuli. Although both allergen exposure and parasite infections frequently occur in the genital area, the mechanism by which immune responses-particularly type 2 immunity-are induced has rarely been studied in the genital mucosa. Here, we demonstrate the induction of T helper type 2 (Th2) immunity in the genital mucosa in response to a model allergen, the protease papain. Intravaginal papain immunization induced type 2 immunity in a manner that was dependent on protease activity and the estrous phase of the mice. In addition, IL-33 was released from the vaginal epithelia after intravaginal papain immunization, leading to the activation of type 2 innate lymphoid cells (ILC2s). Moreover, the IL-33-MyD88 (myeloid differentiation primary response gene 88) signaling pathway was critical for the induction of type 2 immunity. We also found that Th2 differentiation in response to intravaginal papain treatment requires a specific dendritic cell (DC) subset that is controlled by interferon regulatory factor 4 (IRF4). These findings suggest that type 2 immunity is induced by a unique mechanism in the genital tract, which is an important, but often overlooked, barrier surface.

Genital tract

10.1073/pnas.1612997114

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Citations (13)

TAK1 regulates autophagic cell death by suppressing the phosphorylation of p70 S6 kinase 1

Scientific Reports (2013)

Ju Hyun Shin Sang Hyun Min Seong‐Jin Kim Young‐Il Kim Junsoo Park

There is growing interest in identifying regulators of autophagy. The molecular mechanism underlying transforming growth factor-β activated kinase 1 (TAK1)-induced autophagy is poorly understood. We found that TAK1 inhibits p70 S6 kinase1 (S6K1) phosphorylation by interfering interaction of raptor with S6K1, thus inducing autophagy. The factors that determine whether autophagy is cytoprotective or cytotoxic have not been fully elucidated. In Drosophila, TAK1 overexpression leads to an impaired eye phenotype despite inhibition of apoptosis, indicating that the phenotype was mainly due to autophagy. Also, TAK1 overexpression increases lactate dehydrogenase (LDH) level in mammalian cells. When treated with autophagy inhibitors, the level of TAK1-induced cytotoxicity or cell death was significantly attenuated, indicating that TAK1 induces cytotoxic autophagic cell death. This study provides the first in vitro and in vivo evidence of TAK1-induced autophagy and we believe that our findings significantly contribute to the understanding of the mechanisms underlying the induction of autophagy.

10.1038/srep01561

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Citations (37)

OASL1 deficiency promotes antiviral protection against genital herpes simplex virus type 2 infection by enhancing type I interferon production

Scientific Reports (2016)

Ji Eun Oh Myeong Sup Lee Young-Joon Kim Heung Kyu Lee

Abstract Type I interferon (IFN) interferes with virus replication, promotes antiviral responses and controls innate and adaptive immune responses to certain viruses. Recently, we reported that 2’–5’ oligoadenylate synthetase-like 1 (OASL1) negatively regulates type I IFN production by inhibiting the translation of the type I IFN-regulating master transcription factor, IRF7. Notably, while OASL1-deficient mice induce robust production of type I IFN and are resistant to systemic viral infection, the effects of OASL1 during localized viral infection has not been studied. To this end, we investigated the role of OASL1 during mucosal HSV-2 infection of the genital tract. Oasl1 −/− mice exhibited better survival rates than wild type (WT) mice following intravaginal HSV-2 infection and suppressed virus replication more efficiently despite comparable recruitment of effector immune cells. Moreover, Ly6C high monocytes and not pDCs or other cell types, displayed enhanced production of type I IFNs in Oasl1 −/− mice in response to HSV-2 infection. Furthermore, cytotoxic T cell responses including IFN-γ production were accelerated in Oasl1 −/− mice after mucosal HSV-2 infection. Collectively, these results demonstrate that OASL1 deficiency promotes antiviral immunity against local mucosal viral infection and suggest that OASL1 could be a therapeutic target for treatment of HSV-2 infection of the genital mucosa.

IRF7

10.1038/srep19089

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Citations (21)

Defective mitochondrial fission augments NLRP3 inflammasome activation

Scientific Reports (2015)

Sangjun Park Ji-Hee Won Inhwa Hwang Sujeong Hong Heung Kyu Lee

Abstract Despite the fact that deregulated NLRP3 inflammasome activation contributes to the pathogenesis of chronic inflammatory or metabolic disorders, the underlying mechanism by which NLRP3 inflammasome signaling is initiated or potentiated remains poorly understood. Much attention is being paid to mitochondria as a regulator of NLRP3 inflammasome activation, but little is known about the role of mitochondrial dynamics for the inflammasome pathway. Here, we present evidence that aberrant mitochondrial elongation caused by the knockdown of dynamin-related protein 1 (Drp1) lead to a marked increase in NLRP3-dependent caspase-1 activation and interleukin-1-beta secretion in mouse bone marrow-derived macrophages. Conversely, carbonyl cyanide m -chlorophenyl hydrazone, a chemical inducer of mitochondrial fission, clearly attenuated NLRP3 inflammasome assembly and activation. Augmented activation of NLRP3 inflammasome by mitochondrial elongation is not resulted from the increased mitochondrial damages of Drp1-knockdown cells. Notably, enhanced extracellular signal-regulated kinase (ERK) signaling in Drp1-knockdown macrophages is implicated in the potentiation of NLRP3 inflammasome activation, possibly via mediating mitochondrial localization of NLRP3 to facilitate the assembly of NLRP3 inflammasome. Taken together, our results provide a molecular insight into the importance of mitochondrial dynamics in potentiating NLRP3 inflammasome activation, leading to aberrant inflammation.

DNM1L

AIM2

Mitochondrial ROS

Pyroptosis

10.1038/srep15489

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Citations (143)

Blood monocyte-derived CD169+ macrophages contribute to antitumor immunity against glioblastoma

Nature Communications (2022)

Hyun-Jin Kim Jang Hyun Park Hyeon Cheol Kim Chae Won Kim In Kang

Abstract Infiltrating tumor-associated macrophages (TAM) are known to impede immunotherapy against glioblastoma (GBM), however, TAMs are heterogeneous, and there are no clear markers to distinguish immunosuppressive and potentially immune-activating populations. Here we identify a subset of CD169 + macrophages promoting an anti-tumoral microenvironment in GBM. Using single-cell transcriptome analysis, we find that CD169 + macrophages in human and mouse gliomas produce pro-inflammatory chemokines, leading to the accumulation of T cells and NK cells. CD169 expression on macrophages facilitates phagocytosis of apoptotic glioma cells and hence tumor-specific T cell responses. Depletion of CD169 + macrophages leads to functionally impaired antitumor lymphocytes and poorer survival of glioma-bearing mice. We show that NK-cell-derived IFN-γ is critical for the accumulation of blood monocyte-derived CD169 + macrophages in gliomas. Our work thus identifies a well-distinguished TAM subset promoting antitumor immunity against GBM, and identifies key factors that might shift the balance from immunosuppressive to anti-tumor TAM.

Monocyte

10.1038/s41467-022-34001-5

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Citations (35)

Hassall's corpuscles instruct dendritic cells to induce CD4+CD25+ regulatory T cells in human thymus

Nature (2005)

Norihiko Watanabe Yi-Hong Wang Heung Kyu Lee Tomoki� Ito Yui-Hsi Wang

10.1038/nature03886

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Citations (748)