July 2018
Volume 59, Issue 9
Open Access
ARVO Annual Meeting Abstract  |   July 2018
Dendritic cell-specific Syk/Card9-signaling is essential for induction of autoimmune uveitis
Author Affiliations & Notes
  • Holly Rosenzweig
    Molecular Microbiology & Immunology, Oregon Health & Science University/Portland VA Medical Center, Portland, Oregon, United States
  • Ruth Napier
    Molecular Microbiology & Immunology, Oregon Health & Science University/Portland VA Medical Center, Portland, Oregon, United States
  • Paige Snow
    Molecular Microbiology & Immunology, Oregon Health & Science University/Portland VA Medical Center, Portland, Oregon, United States
  • Kimberly Samson
    Molecular Microbiology & Immunology, Oregon Health & Science University/Portland VA Medical Center, Portland, Oregon, United States
  • Emily Vance
    Molecular Microbiology & Immunology, Oregon Health & Science University/Portland VA Medical Center, Portland, Oregon, United States
  • Rachel R Caspi
    Laboratory of Immunology, NEI, Bethesda, Maryland, United States
  • Ellen J Lee
    Molecular Microbiology & Immunology, Oregon Health & Science University/Portland VA Medical Center, Portland, Oregon, United States
  • Footnotes
    Commercial Relationships   Holly Rosenzweig, None; Ruth Napier, None; Paige Snow, None; Kimberly Samson, None; Emily Vance, None; Rachel Caspi, None; Ellen Lee, None
  • Footnotes
    Support  EY025250
Investigative Ophthalmology & Visual Science July 2018, Vol.59, 2549. doi:
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    • Get Citation

      Holly Rosenzweig, Ruth Napier, Paige Snow, Kimberly Samson, Emily Vance, Rachel R Caspi, Ellen J Lee; Dendritic cell-specific Syk/Card9-signaling is essential for induction of autoimmune uveitis. Invest. Ophthalmol. Vis. Sci. 2018;59(9):2549.

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      © ARVO (1962-2015); The Authors (2016-present)

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Abstract

Purpose : We previously identified the innate immune receptor Mincle, a C-type lectin receptor (CLR) that signals through Syk and Card9, as essential for the induction of experimental autoimmune uveitis (EAU). Here, we sought to define the underlying cellular effectors that are responsible for the Syk/Card9-coupled signaling pathway in EAU.

Methods : Wild-type C57BL/6J mice or mice deficient in Card9 (Card9 KO) were immunized with interphotoreceptor retinoid-binding protein (IRBP) and IRBP1-20 peptide, and uveitis was evaluated by fundoscopy and histology. The cell lineage essential for Card9 function was evaluated in bone marrow (BM) chimeric mice immunized for EAU and T cell-intrinsic role was evaluated in Rag1 KO mice reconstituted with WT or Card9 KO CD4+ T cells and immunized for EAU. Syk, a kinase upstream of Card9, was inhibited by piceatannol treatment (i.p., q4d) during the inductive (0-14d) or expression (14-21d) phase of EAU. Cellular control of Syk-mediated signaling was evaluated in various APC types by using conditional KO mice that lack Syk in CD11c+ dendritic cells (DC) or LysM+ macrophage/granulocytes, or by using µMT mice lacking B cells due to disruption in IgM of the B cell receptor (BCR), as the BCR is known to signal through Syk. IRBP-induced IL-17 production from in vitro autologous APC/T cell criss-cross experiments was measured by ELISA. Data were analyzed by Mann-Whitney or Student’s t test (n≥6 mice/group, repeated at least once). Significance was considered with p<0.05.

Results : Studies with BM chimeric and Rag1 KO mice supported a myeloid, rather than T cell -intrinsic function for Card9 in controlling development of EAU. Uveitis was not impacted by mutation of the BCR of B cells, which can function as APCs. Inhibition of Syk during the inductive, but not expression, phase of disease abrogated EAU, supporting need for early activation of the Card9/Syk pathway. Finally, Syk-deficiency in DC, but not in macrophage/granulocytes, significantly reduced EAU (p=0.012). In vitro autologous co-cultures also supported Syk-signaling in DC for promotion of IRBP-induced IL-17 production.

Conclusions : These studies uncover an essential inductive role for DC-specific Syk/Card9-coupled signaling that promotes development of EAU.

This is an abstract that was submitted for the 2018 ARVO Annual Meeting, held in Honolulu, Hawaii, April 29 - May 3, 2018.

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