Mincle, the receptor for mycobacterial cord factor, forms a functional receptor complex with <scp>MCL</scp> and <scp>F</scp>cε<scp>RI</scp>‐γ

Lobato‐Pascual, Ana; Saether, Per C.; Fossum, Sigbjørn; Dissen, Erik; Daws, Michael R.

doi:10.1002/eji.201343752

Cited by 115 publications

(109 citation statements)

References 29 publications

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“…3). Thus, although the reported formation of Mcl-Mincle heterodimers may alter the scope and efficiency of ligand recognition (19,54), it is not essential for TDB/TDM-induced macrophage activation. Our results regarding the enhanced responsiveness of TLRprimed macrophages shed some light on the controversial involvement of the TLR adapter protein MYD88 in the response to TDM.…”

Section: Discussionmentioning

confidence: 96%

“…Recently, the CLR Mcl, encoded by the Clec4d gene located next to Clec4e, was identified as second receptor for TDB/TDM, whose main function may be to increase expression of Mincle for full responsiveness (17). Mcl is a phagocytic receptor (18) and can form heterodimers with Mincle (19). Downstream signaling of Mincle, which lacks an internal signaling motif, requires the adaptor FcR g-chain (Fcer1g, FcRg) (20).…”

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confidence: 99%

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Differential Control of Mincle-Dependent Cord Factor Recognition and Macrophage Responses by the Transcription Factors C/EBPβ and HIF1α

Schoenen

Huber

Sonda

et al. 2014

The Journal of Immunology

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Trehalose-6,6-dimycolate (TDM), the mycobacterial cord factor, and its synthetic analog Trehalose-6,6-dibehenate (TDB) bind to the C-type lectin receptors macrophage-inducible C-type lectin (Mincle) and Mcl to activate macrophages. Genetically, the transcriptional response to TDB/TDM has been defined to require FcRγ-Syk-Card9 signaling. However, TDB/TDM-triggered kinase activation has not been studied well, and it is largely unknown which transcriptional regulators bring about inflammatory gene expression. In this article, we report that TDB/TDM caused only weak Syk-phosphorylation in resting macrophages, consistent with low basal Mincle expression. However, LPS-priming caused MYD88-dependent upregulation of Mincle, resulting in enhanced TDB/TDM-induced kinase activation and more rapid inflammatory gene expression. TLR-induced Mincle expression partially circumvented the requirement for Mcl in the response to TDB/TDM. To dissect transcriptional responses to TDB/TDM, we mined microarray data and identified early growth response (Egr) family transcription factors as direct Mincle target genes, whereas upregulation of Cebpb and Hif1a required new protein synthesis. Macrophages and dendritic cells lacking C/EBPβ showed nearly complete abrogation of TDB/TDM responsiveness, but also failed to upregulate Mincle. Retroviral rescue of Mincle expression in Cebpb-deficient cells restored induction of Egr1, but not of G-CSF. This pattern of C/EBPβ dependence was also observed after stimulation with the Dectin-1 ligand Curdlan. Inducible expression of hypoxia-inducible factor 1α (HIF1α) also required C/EBPβ. In turn, HIF1α was not required for Mincle expression, kinase activation, and Egr1 or Csf3 expression, but critically contributed to NO production. Taken together, we identify C/EBPβ as central hub in Mincle expression and inflammatory gene induction, whereas HIF1α controls Nos2 expression. C/EBPβ also connects TLR signals to cord factor responsiveness through MYD88-dependent upregulation of Mincle.

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Section: Discussionmentioning

confidence: 96%

mentioning

confidence: 99%

Differential Control of Mincle-Dependent Cord Factor Recognition and Macrophage Responses by the Transcription Factors C/EBPβ and HIF1α

Schoenen

Huber

Sonda

et al. 2014

The Journal of Immunology

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“…MCL and Dectin-2 form a heteromeric complex to enhance their ability to recognize fungus (16). MCL is also reported to associate with Mincle, and the coexpression of MCL with Mincle increases the expression of Mincle (17). However, the physiological significance of this interaction has not been clear.…”

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confidence: 99%

C-Type Lectin Receptor MCL Facilitates Mincle Expression and Signaling through Complex Formation

Miyake

Oh‐hora

Yamasaki

2015

The Journal of Immunology

112

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C-type lectin receptors expressed in APCs are recently defined pattern recognition receptors that play a crucial role in immune responses against pathogen-associated molecular patterns. Among pathogen-associated molecular patterns, cord factor (trehalose-6,6′-dimycolate [TDM]) is the most potent immunostimulatory component of the mycobacterial cell wall. Two C-type lectin receptors, macrophage-inducible C-type lectin (Mincle) and macrophage C-type lectin (MCL), are required for immune responses against TDM. Previous studies indicate that MCL is required for TDM-induced Mincle expression. However, the mechanism by which MCL induces Mincle expression has not been fully understood. In this study, we demonstrate that MCL interacts with Mincle to promote its surface expression. After LPS or zymosan stimulation, MCL-deficient bone marrow–derived dendritic cells (BMDCs) had a lower level of Mincle protein expression, although mRNA expression was comparable with wild-type BMDCs. Meanwhile, BMDCs from MCL transgenic mice showed an enhanced level of Mincle expression on the cell surface. MCL was associated with Mincle through the stalk region and this region was necessary and sufficient for the enhancement of Mincle expression. This interaction appeared to be mediated by the hydrophobic repeat of MCL, as substitution of four hydrophobic residues within the stalk region with serine (MCL4S) abolished the function to enhance the surface expression of Mincle. MCL4S mutant failed to restore the defective TDM responses in MCL-deficient BMDCs. These results suggest that MCL positively regulates Mincle expression through protein–protein interaction via its stalk region, thereby magnifying Mincle-mediated signaling.

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“…MCL recognition of TDM induces Mincle expression and thus enhances host innate responses (15,17,18). Moreover, MCL is able to form a receptor complex with Mincle (19)(20)(21) to facilitate surface expression of the latter (19). Consequently, MCL is critically involved in TDM-induced experimental autoimmune encephalomyelitis (EAE) (15) and plays a nonredundant role in antimycobacterial innate immunity (17).…”

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confidence: 99%

The C-Type Lectin Receptor MCL Mediates Vaccine-Induced Immunity against Infection with Blastomyces dermatitidis

Wang

Klein

et al. 2016

Infect Immun

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Vaccination is one of the greatest achievements in medicine and a powerful tool to protect humans against infectious diseases. The current armamentarium and efficacy of antifungal drugs is limited; thus, fungal vaccines are urgently needed (1). Today's vaccines against infectious diseases preferentially induce protective antibodies, driven by adjuvants such as alum, which has been used in a clinical trial of vaccination against Candida albicans with a recombinant fungal antigen (2). However, accumulating evidence suggests that antibodies contribute less to antifungal host defense than cellular immunity, which is required to resolve most fungal infections (3-5). Vaccine-induced resistance to fungi requires CD4 ϩ T cells that produce the proinflammatory cytokines interleukin-17 (IL-17; Th17 cells) and gamma interferon (IFN-␥; Th1 cells) (3, 4). While Th1 cells may be dispensable for vaccineinduced immunity against infection with systemic dimorphic fungi in murine models, Th17 cells generally are required for resistance against these infections (3). Hence, the identification of host pathogen recognition receptors (PRR) and signaling pathways that lead to the induction of vaccine-induced Th17 cell responses is critical for the rational design of antifungal vaccines.C-type lectin receptors (CLRs) represent a large family of PRRs that share structurally homologous carbohydrate recognition domain(s) (CRD) (6, 7). CLRs expressed on antigen-presenting cells recognize carbohydrate structures on the fungal cell wall and tailor adaptive responses via the instruction of CD4 ϩ T helper cells (1,8,9). In a murine model of subcutaneous vaccination, we have previously uncovered an essential role of Dectin-2 in inducing antifungal immunity and CD4 ϩ T cell development (10). Using a reporter cell assay, we showed that Dectin-2 directly binds to vaccine yeast and triggers downstream NFAT signaling. Animals lacking Dectin-2 or its adaptor, FcR␥, fail to differentiate and recruit Th1/Th17 cells to the lung upon recall, and consequently the mice lack the ability to acquire vaccine-induced resistance.MCL (also known as Dectin-3, CLECSF8, and CLEC4D) is a recently described Dectin-2 family member (11). It was originally cloned from macrophages (12) and later found to be expressed in other myeloid cell types, including monocytes and various subsets of dendritic cells (13,14). Like Dectin-2, MCL is a type II transmembrane protein with a single extracellular CRD, and it associates with FcR␥ to trigger intracellular signaling (15). Recent studies have shown that MCL recognizes mycobacterial cord factor TDM (trehalose-6,6=-dimycolate) (15, 16), a glycolipid ligand also recognized by another Dectin-2 family member, Mincle. MCL recognition of TDM induces Mincle expression and thus enhances host innate responses (15,17,18). Moreover, MCL is able to form a receptor complex with Mincle (19-21) to facilitate surface expression of the latter (19). Consequently, MCL is critically involved in TDM-induced experimental autoimmune encephalomyelitis (EAE...

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Mincle, the receptor for mycobacterial cord factor, forms a functional receptor complex with MCL and FcεRI‐γ

Cited by 115 publications

References 29 publications

Differential Control of Mincle-Dependent Cord Factor Recognition and Macrophage Responses by the Transcription Factors C/EBPβ and HIF1α

Differential Control of Mincle-Dependent Cord Factor Recognition and Macrophage Responses by the Transcription Factors C/EBPβ and HIF1α

C-Type Lectin Receptor MCL Facilitates Mincle Expression and Signaling through Complex Formation

The C-Type Lectin Receptor MCL Mediates Vaccine-Induced Immunity against Infection with Blastomyces dermatitidis

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