<scp>ADAM</scp>10 and Notch1 on murine dendritic cells control the development of type 2 immunity and IgE production

Damle, Sheela R.; Martin, Rebecca; Cockburn, Chelsea L.; Lownik, Joseph C.; Carlyon, Jason A.; Smith, Allen; Conrad, Daniel H.

doi:10.1111/all.13261

Cited by 20 publications

(21 citation statements)

References 40 publications

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“…Notably, Notch signaling has been reported to be crucial during CD8α − cDC differentiation (23). Furthermore, a recent report that studied mice in which DC-specific depletion of ADAM10 revealed that ADAM10-mediated Notch signaling was crucial for TH2 allergic lung inflammation (24). However, the role of ADAM10 during cDC differentiation has yet to be elucidated.…”

Section: Significancementioning

confidence: 99%

Cell-autonomous FLT3L shedding via ADAM10 mediates conventional dendritic cell development in mouse spleen

Fujita

Chakarov

Kobayashi

et al. 2019

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

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Conventional dendritic cells (cDCs) derive from bone marrow (BM) precursors that undergo cascades of developmental programs to terminally differentiate in peripheral tissues. Pre-cDC1s and pre-cDC2s commit in the BM to each differentiate into CD8α+/CD103+ cDC1s and CD11b+ cDC2s, respectively. Although both cDCs rely on the cytokine FLT3L during development, mechanisms that ensure cDC accessibility to FLT3L have yet to be elucidated. Here, we generated mice that lacked a disintegrin and metalloproteinase (ADAM) 10 in DCs (Itgax-cre × Adam10-fl/fl; ADAM10∆DC) and found that ADAM10 deletion markedly impacted splenic cDC2 development. Pre-cDC2s accumulated in the spleen with transcriptomic alterations that reflected their inability to differentiate and exhibited abrupt failure to survive as terminally differentiated cDC2s. Induced ADAM10 ablation also led to the reduction of terminally differentiated cDC2s, and restoration of Notch signaling, a major pathway downstream of ADAM10, only modestly rescued them. ADAM10∆DC BM failed to generate cDC2s in BM chimeric mice with or without cotransferred ADAM10-sufficient BM, indicating that cDC2 development required cell-autonomous ADAM10. We determined cDC2s to be sources of soluble FLT3L, as supported by decreased serum FLT3L concentration and the retention of membrane-bound FLT3L on cDC2 surfaces in ADAM10∆DC mice, and by demonstrating the release of soluble FLT3L by cDC2 in ex vivo culture supernatants. Through in vitro studies utilizing murine embryonic fibroblasts, we determined FLT3L to be a substrate for ADAM10. These data collectively reveal cDC2s as FLT3L sources and highlight a cell-autonomous mechanism that may enhance FLT3L accessibility for cDC2 development and survival.

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Section: Significancementioning

confidence: 99%

Cell-autonomous FLT3L shedding via ADAM10 mediates conventional dendritic cell development in mouse spleen

Fujita

Chakarov

Kobayashi

et al. 2019

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

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“…Targeting Notch1 signaling on DCs has been proposed as a novel strategy for modulating Th2 immune responses ( 31 ). So, we evaluated if Notch1 signaling was necessary for the LACK 156–173 epitope to polarize DCs, by using siRNA to silence Jagged1 expression in BMDCs, which were cultured from bone marrow cells of BALB/c mice.…”

Section: Resultsmentioning

confidence: 99%

A Single Microorganism Epitope Attenuates the Development of Murine Autoimmune Arthritis: Regulation of Dendritic Cells via the Mannose Receptor

et al. 2018

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A single epitope of Leishmania analog of the receptors for activated C kinase (LACK) from Leishmania major, the polypeptide LACK156–173, is recognized by Vβ4+/Vα8+ T cells, and activate these cells that drives the subsequent T helper (Th)2 response. This study was undertaken to investigate the therapeutic potential of the LACK156–173 epitope in murine autoimmune arthritis models. To explore the influence of the LACK156–173 epitope on murine collagen antibody-induced arthritis, as well as its immunological mechanism, we vaccinated or treated mice with a LACK156–173 epitope expression plasmid or polypeptide. The effect of LACK156–173 epitope was then evaluated by clinical scores, histopathology, and quantitative real-time polymerase chain reaction (qRT-PCR) analysis. Using flow cytometry, we measured the subsets and maturity of CD11c+ dendritic cells (DCs), as well as T cell polarization, in co-culture experiments. We also measured cytokine gene expression and production. The murine macrophage-like cell line RAW264.7 was used to identify the receptor for the epitope. Vaccination or treatment of the mice with the LACK156–173 epitope expression plasmid or polypeptide ameliorated the severity of arthritis. qRT-PCR analysis revealed that the LACK156–173 epitope improved the balance of effector T cells in synovial tissue compared to that in untreated arthritis controls. Toll-like receptor (TLR) 4 expression was diminished by LACK156–173. The epitope also influenced T cell polarization by regulating the differentiation, maturation, and functions of CD11c+ DCs and upregulating Jagged1 ligand expression. Blocking the mannose receptor (MR) significantly attenuated LACK156–173 epitope-induced macrophage activation. Our data indicate that vaccination or treatment with a single microorganism epitope, LACK156–173, is a highly efficient therapy for murine autoimmune arthritis. The therapeutic effects are mediated by the regulation of the differentiation, maturation, and functions of DCs via MR, resulting in the upregulation of Jagged1 expression and Th2 cell polarization. Our results demonstrate the therapeutic potential of the LACK156–173 epitope in rheumatoid arthritis.

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“…Dendritic cell-specific ADAM10-knockout mice have been generated by crossing ADAM10 floxed mice with CD11c-Cre mice ( 62 ). These mice have strikingly impaired Th2 responses, but Th1 and Th17 responses are unaffected.…”

Section: Regulation Of Myeloid Cell Function By Adam10 and Potential mentioning

confidence: 99%

“…As a consequence, the mice are protected from IgE-mediated anaphylaxis and allergic lung inflammation. This appears to be due to defective Notch signaling, since rescue is observed by transgenic expression of the Notch1 intracellular domain, and dendritic cell-specific Notch1-knockout mice have a similar phenotype ( 62 ). Our RNA-Seq analyses have found Tspan14 to be most highly expressed in human dendritic cells, with lower expression of Tspan17 and Tspan33 (data not shown).…”

Section: Regulation Of Myeloid Cell Function By Adam10 and Potential mentioning

confidence: 99%

Regulation of Leukocytes by TspanC8 Tetraspanins and the “Molecular Scissor” ADAM10

et al. 2018

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A disintegrin and metalloproteinase 10 (ADAM10) is a ubiquitous transmembrane protein that functions as a “molecular scissor” to cleave the extracellular regions from its transmembrane target proteins. ADAM10 is well characterized as the ligand-dependent activator of Notch proteins, which control cell fate decisions. Indeed, conditional knockouts of ADAM10 in mice reveal impaired B-, T-, and myeloid cell development and/or function. ADAM10 cleaves many other leukocyte-expressed substrates. On B-cells, ADAM10 cleavage of the low-affinity IgE receptor CD23 promotes allergy and asthma, cleavage of ICOS ligand impairs antibody responses, and cleavage of the BAFF–APRIL receptor transmembrane activator and CAML interactor, and BAFF receptor, reduce B-cell survival. On microglia, increased ADAM10 cleavage of a rare variant of the scavenger receptor triggering receptor expressed on myeloid cells 2 may increase susceptibility to Alzheimer’s disease. We and others recently showed that ADAM10 interacts with one of six different regulatory tetraspanin membrane proteins, which we termed the TspanC8 subgroup, comprising Tspan5, Tspan10, Tspan14, Tspan15, Tspan17, and Tspan33. The TspanC8s are required for ADAM10 exit from the endoplasmic reticulum, and emerging evidence suggests that they dictate ADAM10 subcellular localization and substrate specificity. Therefore, we propose that ADAM10 should not be regarded as a single scissor, but as six different scissors with distinct substrate specificities, depending on the associated TspanC8. In this review, we collate recent transcriptomic data to present the TspanC8 repertoires of leukocytes, and we discuss the potential role of the six TspanC8/ADAM10 scissors in leukocyte development and function.

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ADAM10 and Notch1 on murine dendritic cells control the development of type 2 immunity and IgE production

Abstract: Targeting ADAM10 and Notch1 on DCs represent a novel strategy for modulating T 2 immune responses and IgE production.

Cited by 20 publications

References 40 publications

Cell-autonomous FLT3L shedding via ADAM10 mediates conventional dendritic cell development in mouse spleen

Cell-autonomous FLT3L shedding via ADAM10 mediates conventional dendritic cell development in mouse spleen

A Single Microorganism Epitope Attenuates the Development of Murine Autoimmune Arthritis: Regulation of Dendritic Cells via the Mannose Receptor

Regulation of Leukocytes by TspanC8 Tetraspanins and the “Molecular Scissor” ADAM10

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