Mincle-mediated translational regulation is required for strong nitric oxide production and inflammation resolution

Lee, Wook Bin; Kang, Ji Seon; Choi, Won Young; Zhang, Quanri; Kim, Chul Han; Choi, Un Yung; Kim-Ha, Jeongsil; Kim, Young-Joon

doi:10.1038/ncomms11322

Cited by 54 publications

(53 citation statements)

References 66 publications

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“…7). First, we observed that the TLR2-driven induction of Mincle surface expression is operative and consistent with data from previous reports on TLR4 action (37,40), MyD88-dependent upregulation in response to Mycobacterium bovis BCG (42), and TLR2 activity (43). This C/EBP␤-dependent feed-forward loop enhancing the response to Mincle ligands (37) most likely accounts for the TLR2-driven G-CSF production in response to cell wall glycolipid challenge, although we acknowledge that formal proof of this mechanism would require the demonstration that the overexpression of Mincle, perhaps in association with other CLRs like Mcl, circumvents TLR2 dependence.…”

Section: Discussionsupporting

confidence: 91%

“…Indeed, the Mincle ligand TDM inhibited interleukin-12p40 (IL-12p40) production induced by the TLR2 ligand Pam3CSK4 via IL-10 production in murine macrophages (45), and Wevers et al observed that the ligation of Mincle downregulated IL-12p35 expression induced by TLR or Dectin-1 stimulation via phosphatidylinositol 3-kinase (PI3K)-protein kinase B (PKB)-dependent MDM2-mediated degradation of IRF-1 in human dendritic cells (DC) (46). An interesting mechanism for the synergistic induction of the iNOS protein by TDM and Pam3CSK4 through increased translational efficiency dependent on hypusination of the elongation factor eukaryotic initiation factor 5 (eIF5) was recently described by Lee and colleagues (43). Thus, it will be interesting to investigate the differential regulation of a wider set of inflammatory and regulatory cytokines by Mincle and TLR2 pathways after macrophages encounter corynebacteria.…”

Section: Discussionmentioning

confidence: 95%

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Toll-Like Receptor 2 and Mincle Cooperatively Sense Corynebacterial Cell Wall Glycolipids

et al. 2017

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Nontoxigenic Corynebacterium diphtheriae and Corynebacterium ulcerans cause invasive disease in humans and animals. Host sensing of corynebacteria is largely uncharacterized, albeit the recognition of lipoglycans by Toll-like receptor 2 (TLR2) appears to be important for macrophage activation by corynebacteria. The members of the order Corynebacterineae (e.g., mycobacteria, nocardia, and rhodococci) share a glycolipid-rich cell wall dominated by mycolic acids (termed corynomycolic acids in corynebacteria). The mycolic acid-containing cord factor of mycobacteria, trehalose dimycolate, activates the C-type lectin receptor (CLR) Mincle. Here, we show that glycolipid extracts from the cell walls of several pathogenic and nonpathogenic Corynebacterium strains directly bound to recombinant Mincle in vitro. Macrophages deficient in Mincle or its adapter protein Fc receptor gamma chain (FcR␥) produced severely reduced amounts of granulocyte colony-stimulating factor (G-CSF) and of nitric oxide (NO) upon challenge with corynebacterial glycolipids. Consistently, cell wall extracts of a particular C. diphtheriae strain (DSM43989) lacking mycolic acid esters neither bound Mincle nor activated macrophages. Furthermore, TLR2 but not TLR4 was critical for sensing of cell wall extracts and whole corynebacteria. The upregulation of Mincle expression upon encountering corynebacteria required TLR2. Thus, macrophage activation by the corynebacterial cell wall relies on TLR2-driven robust Mincle expression and the cooperative action of both receptors.KEYWORDS C-type lectin receptor, Mincle, Toll-like receptor, macrophage, Corynebacterium diphtheriae, cell wall lipids, mycolate, mycolic acid, corynomycolate D iphtheria caused by toxin-producing Corynebacterium diphtheriae is a severe, life-threatening infection, which has become rare in Europe due to the efficacy and coverage of toxoid immunization but still causes a considerable burden of disease globally. Corynebacterium ulcerans and Corynebacterium pseudotuberculosis can also harbor the tox gene encoding diphtheria toxin (1) and in addition may secrete the exotoxin phospholipase D, a virulence factor involved in caseous lymphadenitis of sheep and goats (2, 3). Rates of infections with nontoxigenic strains of C. diphtheriae, including bloodstream infections and endocarditis, appear to be increasing in Europe (4,5). Of the 90 species that comprise the genus Corynebacterium, many inhabit the human skin or mucosa as commensals (6), with C. striatum, C. tuberculostearicum, C. amycolatum, and C. jeikeium being typical examples of skin inhabitants, whereas C. urealyticum and C. glucuronolyticum are frequently found in the urogenital tract. All

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Section: Discussionsupporting

confidence: 91%

Section: Discussionmentioning

confidence: 95%

Toll-Like Receptor 2 and Mincle Cooperatively Sense Corynebacterial Cell Wall Glycolipids

et al. 2017

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“…Mouse neutrophils from bone marrow were separated using a Percoll density gradient, as previously described2324. Neutrophils were suspended in RPMI-1640 medium supplemented with 5% fetal calf serum.…”

Section: Methodsmentioning

confidence: 99%

“…RNA sequencing analysis was performed as previously described23. The GEO accession number for the RNA sequencing data reported in this paper is GSE70793.…”

Section: Methodsmentioning

confidence: 99%

“…In particular, stimulation with LPS or trehalose 6-dimycolate (TDM) induces high expression of Mincle (macrophage-inducible C-type lectin, also designated Clec4e or Clecsf9) on the surface of macrophages, dendritic cells, and neutrophils212223242526. Mincle-deficient mice exhibit defective clearing of Candida albicans 27 and reduced production of TNF-α and CXCL2 along with defects in neutrophil infiltration in response to Malasezzia fungal infection26.…”

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confidence: 99%

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Mincle activation enhances neutrophil migration and resistance to polymicrobial septic peritonitis

Lee

Yan

Kang

et al. 2017

Sci Rep

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Sepsis is a systemic inflammatory response to bacterial infection. The therapeutic options for treating sepsis are limited. Impaired neutrophil recruitment into the infection site is directly associated with severe sepsis, but the precise mechanism is unclear. Here, we show that Mincle plays a key role in neutrophil migration and resistance during polymicrobial sepsis. Mincle-deficient mice exhibited lower survival rates in experimental sepsis from cecal ligation and puncture and Escherichia coli–induced peritonitis. Mincle deficiency led to higher serum inflammatory cytokine levels and reduced bacterial clearance and neutrophil recruitment. Transcriptome analyses revealed that trehalose dimycolate, a Mincle ligand, reduced the expression of G protein–coupled receptor kinase 2 (GRK2) in neutrophils. Indeed, GRK2 expression was upregulated, but surface expression of the chemokine receptor CXCR2 was downregulated in blood neutrophils from Mincle-deficient mice with septic injury. Moreover, CXCL2-mediated adhesion, chemotactic responses, and F-actin polymerization were reduced in Mincle-deficient neutrophils. Finally, we found that fewer Mincle-deficient neutrophils infiltrated from the blood circulation into the peritoneal fluid in bacterial septic peritonitis compared with wild-type cells. Thus, our results indicate that Mincle plays an important role in neutrophil infiltration and suggest that Mincle signaling may provide a therapeutic target for treating sepsis.

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The Mincle ligand trehalose dibehenate differentially modulates M1‐like and M2‐like macrophage phenotype and function via Syk signaling

Kodar

Harper

McConnell

et al. 2017

Immunity Inflam & Disease

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IntroductionMacrophages play a significant role in the progression of diseases, such as cancer, making them a target for immune‐modulating agents. Trehalose dibehenate (TDB) is known to activate M1‐like macrophages via Mincle, however, the effect of TDB on M2‐like macrophages, which are found in the tumor microenvironment, has not been studied.MethodsqRT‐PCR, flow cytometry, cytokine ELISA, and Western Blotting were used to study the effect of TDB on GM‐CSF and M‐CSF/IL‐4 derived bone marrow macrophages (BMMs) from C57BL/6 and Mincle−/− mice.ResultsTDB treatment up‐regulated M1 markers over M2 markers by GM‐CSF BMMs, whereas M‐CSF/IL‐4 BMMs down‐regulated marker gene expression overall. TDB treatment resulted in Mincle‐independent down‐regulation of CD11b, CD115, and CD206 expression by GM‐CSF macrophages and CD115 in M‐CSF/IL‐4 macrophages. GM‐CSF BMMs produced of significant levels of proinflammatory cytokines (IL‐1β, IL‐6, TNF‐α), which was Mincle‐dependent and further enhanced by LPS priming. M‐CSF BMMs produced little or no cytokines in response to TDB regardless of LPS priming. Western blot analysis confirmed that the absence of cytokine production was associated with a lack of activation of the Syk kinase pathway.ConclusionThis study illustrates that TDB has the potential to differentially regulate M1‐ and M2‐like macrophages in the tumor environment.

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Mincle-mediated translational regulation is required for strong nitric oxide production and inflammation resolution

Cited by 54 publications

References 66 publications

Toll-Like Receptor 2 and Mincle Cooperatively Sense Corynebacterial Cell Wall Glycolipids

Toll-Like Receptor 2 and Mincle Cooperatively Sense Corynebacterial Cell Wall Glycolipids

Mincle activation enhances neutrophil migration and resistance to polymicrobial septic peritonitis

The Mincle ligand trehalose dibehenate differentially modulates M1‐like and M2‐like macrophage phenotype and function via Syk signaling

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