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William Stevenson, Zahra Sadrai, Jing Hua, Shilpa Kodati, Sunil K. Chauhan, Jing-Feng Huang, Reza Dana; Jak1/3 Inhibition Suppresses Acute And Chronic Forms Of Murine Ocular Surface Inflammation. Invest. Ophthalmol. Vis. Sci. 2012;53(14):2342.
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© ARVO (1962-2015); The Authors (2016-present)
To evaluate the therapeutic efficacy of topical Janus kinase (Jak) 1/3 inhibitor tofacitinib (CP-690,550) in acute and chronic forms of ocular surface inflammation.
The therapeutic efficacy of Jak1/3 inhibition was assessed using murine models of corneal thermocautery and dry eye disease (DED). Male BALB/c mice (n = 7-10) aged 6 to 8 weeks were subjected to corneal thermocautery and randomized to receive topical 0.003% Jak1/3 inhibitor or vehicle BID. Corneas were excised on post-thermocautery days 1 and 3 for analyses with flow cytometry and real-time PCR. In a separate study, DED was induced by exposing female C57BL/6 mice (n = 4-5) aged 6 to 8 weeks to desiccating stress and administering anticholinergic agents. Mice were randomized to receive either topical 0.003% Jak1/3 inhibitor BID, 0.003% Jak1/3 inhibitor QD and vehicle QD, vehicle BID, or no treatment for 15 days. Corneal fluorescein staining (CFS) was performed and mice were sacrificed on day 15 for analyses with immunohistochemical staining and real-time PCR.
In the corneal thermocautery experiment, Jak1/3 inhibition decreased the corneal infiltration of CD45+, Gr-1+, and CD11b+ cells on post-thermocautery day 1 (74%, 62%, and 76%, respectively) and day 3 (2.7%, 57%, and 19%, respectively) as compared to vehicle treated corneas. Proinflammatory cytokine IL-1β mRNA expression was significantly decreased (P < 0.05) by Jak1/3 inhibition on day 3 as compared to vehicle treated corneas. In the DED experiment, Jak1/3 inhibition BID significantly decreased CFS scores as compared to vehicle treated and untreated groups (P < 0.05). Expression of the proinflammatory cytokines TNF and IL-23 was significantly decreased (P < 0.05), and anti-inflammatory IL-1RA was significantly increased (P < 0.05) in the Jak1/3 BID group as compared to vehicle treated and untreated groups. Jak1/3 inhibition BID significantly decreased (P < 0.05) the corneal infiltration of CD11b+ antigen-presenting cells (P < 0.05). Jak1/3 inhibition also significantly decreased (P < 0.05) the conjunctival infiltration of pathogenic T helper 17 cells, and significantly increased (P < 0.05) the conjunctival expression of T regulatory cell-associated FoxP3.
Topical Jak1/3 inhibition improves immunoinflammatory profiles in acute and chronic forms of murine ocular surface inflammation.
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