Dendritic cell SIRPα regulates homeostasis of dendritic cells in lymphoid organs

Washio, Ken; Kotani, Takenori; Saito, Yasuyuki; Respatika, Datu; Murata, Yoji; Kaneko, Yoriaki; Okazawa, Hideki; Ohnishi, Hiroshi; Fukunaga, Atsushi; Nishigori, Chikako; Matozaki, Takashi

doi:10.1111/gtc.12238

Cited by 26 publications

(32 citation statements)

References 38 publications

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“…These data are consistent with other reports that CD47 is expressed on virtually all cells, whereas SIRPA is predominantly expressed on phagocytic and neuronal cells, being barely detectable in T or B cells [21, 38-40]. Importantly, live cell imaging system captured a dynamic contact of CD47-stained Treg cells with SIRPA-stained VM neurons in the present study.…”

Section: Discussionsupporting

confidence: 93%

Treg Cells Protect Dopaminergic Neurons against MPP+ Neurotoxicity via CD47-SIRPA Interaction

Huang

Cao

et al. 2017

Cell Physiol Biochem

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Background/Aims: Regulatory T (Treg) cells have been associated with neuroprotection by inhibiting microglial activation in animal models of Parkinson's disease (PD), a progressive neurodegenerative disease characterized by dopaminergic neuronal loss in the nigrostriatal system. Herein, we show that Treg cells directly protect dopaminergic neurons against 1-methyl-4-phenylpyridinium (MPP⁺) neurotoxicity via an interaction between the two transmembrane proteins CD47 and signal regulatory protein α (SIRPA). Methods: Primary ventral mesencephalic (VM) cells or VM neurons were pretreated with Treg cells before MPP⁺ treatment. Transwell co-culture of Treg cells and VM neurons was used to assess the effects of the Treg cytokines transforming growth factor (TGF)-β1 and interleukin (IL)-10 on dopaminergic neurons. Live cell imaging system detected a dynamic contact of Treg cells with VM neurons that were stained with CD47 and SIRPA, respectively. Dopaminergic neuronal loss, which was assessed by the number of tyrosine hydroxylase (TH)-immunoreactive cells, was examined after silencing CD47 in Treg cells or silencing SIRPA in VM neurons. Results: Treg cells prevented MPP⁺-induced dopaminergic neuronal loss and glial inflammatory responses. TGF-β1 and IL-10 secreted from Treg cells did not significantly prevent MPP⁺-induced dopaminergic neuronal loss in transwell co-culture of Treg cells and VM neurons. CD47 and SIRPA were expressed by Treg cells and VM neurons, respectively. CD47-labeled Treg cells dynamically contacted with SIRPA-labeled VM neurons. Silencing CD47 gene in Treg cells impaired the ability of Treg cells to protect dopaminergic neurons against MPP⁺ toxicity. Similarly, SIRPA knockdown in VM neurons reduced the ability of Treg cell neuroprotection. Rac1/Akt signaling pathway in VM neurons was activated by CD47-SIRPA interaction between Treg cells and the neurons. Inhibiting Rac1/Akt signaling in VM neurons compromised Treg cell neuroprotection. Conclusion: Treg cells protect dopaminergic neurons against MPP⁺ neurotoxicity by a cell-to-cell contact mechanism underlying CD47-SIRPA interaction and Rac1/Akt activation.

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Section: Discussionsupporting

confidence: 93%

Treg Cells Protect Dopaminergic Neurons against MPP+ Neurotoxicity via CD47-SIRPA Interaction

Huang

Cao

et al. 2017

Cell Physiol Biochem

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“…We do not exclude that CD47 on additional cell types contributes to maintaining DC quiescence (Saito et al, 2010; Wang et al, 2007). (Saito et al, 2010)CD47 and SIRPα-deficient mice have DC reductions in lymph nodes (LNs), epidermis and lamina propria as well as spleen (Saito et al, 2010; Scott et al, 2014; Washio et al, 2015). Given that DCs in non-splenic locations may not be regularly exposed to RBCs, these deficiencies might indicate that DC interactions with other CD47 + cell types are important, but it is also possible that other functions of SIRPα and CD47 are needed in different DC types (Barclay and Van den Berg, 2014).…”

Section: Discussionmentioning

confidence: 99%

Splenic Dendritic Cells Survey Red Blood Cells for Missing Self-CD47 to Trigger Adaptive Immune Responses

Chen

et al. 2015

Immunity

114

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Summary Sheep red blood cells (SRBCs) have long been used as a model antigen for eliciting systemic immune responses yet the basis for their adjuvant activity has been unknown. Here we show that SRBCs failed to engage the inhibitory mouse SIRPα receptor on splenic CD4+ dendritic cells (DCs), and this led to DC activation. Removal of the SIRPα ligand, CD47, from self-RBCs was sufficient to convert them into an adjuvant for adaptive immune responses. DC capture of Cd47−/− RBCs and DC activation occurred within minutes in a src-family kinase and CD18 integrin-dependent manner. These findings provide an explanation for the adjuvant mechanism of SRBCs and reveal that splenic DCs survey blood cells for missing self-CD47, a process that may contribute to detecting and mounting immune responses against pathogen-infected RBCs.

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“…Pirbdeficient mice show defects in DC maturation, which skews T cell responses [81]. Sirpa may be key for DC survival; mice deficient in Sirpa have reduced numbers of cDCs [91]. Loss of Sirpa in DCs leads to similar responses to those observed following Shp1 inhibition, namely, increased IL-12 production, up-regulation of DC activation markers, increased survival, and enhanced T cell priming [92].…”

Section: Dcsmentioning

confidence: 99%

Shp1 function in myeloid cells

Abram

Lowell

2017

Journal of Leukocyte Biology

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The mouse was first described in 1975 as a model of systemic inflammation and autoimmunity, as a result of immune system dysregulation. The phenotype was later ascribed to mutations in the cytoplasmic tyrosine phosphatase Shp1. This phosphatase is expressed widely throughout the hematopoietic system and has been shown to impact a multitude of cell signaling pathways. The determination of which cell types contribute to the different aspects of the phenotype caused by global Shp1 loss or mutation and which pathways within these cell types are regulated by Shp1 is important to further our understanding of immune system regulation. In this review, we focus on the role of Shp1 in myeloid cells and how its dysregulation affects immune function, which can impact human disease.

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Dendritic cell SIRPα regulates homeostasis of dendritic cells in lymphoid organs

Cited by 26 publications

References 38 publications

Treg Cells Protect Dopaminergic Neurons against MPP+ Neurotoxicity via CD47-SIRPA Interaction

Treg Cells Protect Dopaminergic Neurons against MPP+ Neurotoxicity via CD47-SIRPA Interaction

Splenic Dendritic Cells Survey Red Blood Cells for Missing Self-CD47 to Trigger Adaptive Immune Responses

Shp1 function in myeloid cells

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