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

Miyake, Yoshihiro; Oh‐hora, Masatsugu; Yamasaki, Satoshi

doi:10.4049/jimmunol.1402429

Cited by 108 publications

(102 citation statements)

References 30 publications

(54 reference statements)

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“…GBA1-deficient mice (32) were purchased from the Jackson Laboratory. Mincle Tg mice were previously described (77). GBA1 ΔHPC mice were established as described in Fig.…”

Section: Methodsmentioning

confidence: 99%

Intracellular metabolite β-glucosylceramide is an endogenous Mincle ligand possessing immunostimulatory activity

Nagata

Izumi

Ishikawa

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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137

117

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Sensing and reacting to tissue damage is a fundamental function of immune systems. Macrophage inducible C-type lectin (Mincle) is an activating C-type lectin receptor that senses damaged cells. Notably, Mincle also recognizes glycolipid ligands on pathogens. To elucidate endogenous glycolipids ligands derived from damaged cells, we fractionated supernatants from damaged cells and identified a lipophilic component that activates reporter cells expressing Mincle. Mass spectrometry and NMR spectroscopy identified the component structure as β-glucosylceramide (GlcCer), which is a ubiquitous intracellular metabolite. Synthetic β-GlcCer activated myeloid cells and induced production of inflammatory cytokines; this production was abrogated in Mincle-deficient cells. Sterile inflammation induced by excessive cell death in the thymus was exacerbated by hematopoietic-specific deletion of degrading enzyme of β-GlcCer (β-glucosylceramidase, GBA1). However, this enhanced inflammation was ameliorated in a Mincle-deficient background. GBA1-deficient dendritic cells (DCs) in which β-GlcCer accumulates triggered antigen-specific T-cell responses more efficiently than WT DCs, whereas these responses were compromised in DCs from GBA1 × Mincle double-deficient mice. These results suggest that β-GlcCer is an endogenous ligand for Mincle and possesses immunostimulatory activity.

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“…GBA1-deficient mice (32) were purchased from the Jackson Laboratory. Mincle Tg mice were previously described (77). GBA1 ΔHPC mice were established as described in Fig.…”

Section: Methodsmentioning

confidence: 99%

Intracellular metabolite β-glucosylceramide is an endogenous Mincle ligand possessing immunostimulatory activity

Nagata

Izumi

Ishikawa

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

137

117

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“…Previous studies have shown that Dectin-2's ability to protect the host from fungal infection requires that it form a complex with another CLR member, MCL (or Dectin-3) (14). MCL regulates another CLR, Mincle, by enhancing its cell surface expression (27). Mincle signaling inhibits signal transduction downstream of Dectin-1 (28).…”

Section: Dectin-2-dependent Phagocytotic Activity Of Kupffer Cells Agmentioning

confidence: 99%

The innate immune receptor Dectin-2 mediates the phagocytosis of cancer cells by Kupffer cells for the suppression of liver metastasis

Kimura

Inoue

Hangai

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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Tumor metastasis is the cause of most cancer deaths. Although metastases can form in multiple end organs, the liver is recognized as a highly permissive organ. Nevertheless, there is evidence for immune cell-mediated mechanisms that function to suppress liver metastasis by certain tumors, although the underlying mechanisms for the suppression of metastasis remain elusive. Here, we show that Dectin-2, a C-type lectin receptor (CLR) family of innate receptors, is critical for the suppression of liver metastasis of cancer cells. We provide evidence that Dectin-2 functions in resident macrophages in the liver, known as Kupffer cells, to mediate the uptake and clearance of cancer cells. Interestingly, Kupffer cells are selectively endowed with Dectin-2-dependent phagocytotic activity, with neither bone marrow-derived macrophages nor alveolar macrophages showing this potential. Concordantly, subcutaneous primary tumor growth and lung metastasis are not affected by the absence of Dectin-2. In addition, macrophage C-type lectin, a CLR known to be complex with Dectin-2, also contributes to the suppression of liver metastasis. Collectively, these results highlight the hitherto poorly understood mechanism of Kupffer cell-mediated control of metastasis that is mediated by the CLR innate receptor family, with implications for the development of anticancer therapy targeting CLRs.liver metastasis | C-type lectin receptor | Dectin-2 | Kupffer cell | phagocytosis

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

Cited by 108 publications

References 30 publications

Intracellular metabolite β-glucosylceramide is an endogenous Mincle ligand possessing immunostimulatory activity

Intracellular metabolite β-glucosylceramide is an endogenous Mincle ligand possessing immunostimulatory activity

The innate immune receptor Dectin-2 mediates the phagocytosis of cancer cells by Kupffer cells for the suppression of liver metastasis

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

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