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Jessica Wei, Reiko Horai, Yingyos Jittayasothorn, Mary J Mattapallil, H Nida Sen, Rachel R Caspi, Karsten Gronert; Lipoxin A4 Regulates T Effector Cell Trafficking in Autoimmune Uveitis. Invest. Ophthalmol. Vis. Sci. 2019;60(9):1350. doi: https://doi.org/.
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© ARVO (1962-2015); The Authors (2016-present)
Lipoxin A4 (LXA4) is a small endogenous signaling molecule that regulates leukocyte function and has anti-inflammatory and pro-resolution bioactions in acute inflammation. Despite an impressive body of work, the direct actions of LXA4 on lymphocytes is not well characterized. Previously, we showed that LXA4 treatment ameliorates autoimmune uveitis in mouse models. Here we identify a potential mechanism involved in the regulation of T cell responses by LXA4.
Experimental autoimmune uveitis (EAU) was induced by active immunization with 150 µg IRBP651-670 peptide emulsified in CFA of C57BL/6 WT and 5-LOX KO (Alox5-/-) mice (a KO mouse which does not produce LXA4). For T cell transfer, cells were harvested on day 11 from spleen and lymph nodes of EAU immunized donors and 107 CD3 T cells were transferred intraperitoneally into TCRβ-/- recipients. Three days later, recipients were immunized with IRBP651-670 peptide. Eyes and lymph nodes were collected at peak inflammation for flow cytometry analyses. Antigen-specific T cell responses in vitro were analyzed by 3H thymidine incorporated proliferation assay. CD4 T cells were treated with LXA4 in vitro for 24 hours and analyzed for CCR7 expression by flow cytometry to assess modulation of CCR7 expression by LXA4. LXA4 levels were measured in serum of uveitis patients using ELISA.
LXA4 appeared to inhibit the expression of CCR7, which should result in enhanced emigration of T cells from peripheral lymph nodes to tissues. Funduscopy scores and flow cytometry analyses showed that EAU-immunized Alox5-/- mice had significantly more IFNγ producing ocular cell infiltrates (p=0.0057) in comparison to WT controls at peak inflammation. Similarly, TCRb KO recipients of Alox5-/- T cells developed worse disease in comparison to recipients of WT T cells (p=0.0014). Interestingly, uveitis patient serum (n=36) had significantly higher levels of LXA4 (p=0.03) in comparison to healthy subjects (n=35).
In mouse EAU models, LXA4 attenuates uveitis by regulating expression of T cell trafficking molecules in the periphery, likely affecting the migration of pathogenic T cells to the eye. Additionally, we show the first evidence that the production of protective LXA4 is upregulated in the serum of uveitis patients. Hence, regulation and therapeutic amplification of the endogenous LXA4 pathway may be a potential approach to control the severity of T cell-driven diseases.
This abstract was presented at the 2019 ARVO Annual Meeting, held in Vancouver, Canada, April 28 - May 2, 2019.
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