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Stephen R. Planck, Jordan J. Allensworth, James T. Rosenbaum, Holly L. Rosenzweig; Analysis of the Differential Potential of TLRs to Elicit Uveitis in Mice. Invest. Ophthalmol. Vis. Sci. 2011;52(14):2269.
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Toll-like receptors (TLRs) are critical to host defense and innate immunity. Not only are TLRs important in microbial defense but emerging evidence supports their role in many chronic, inflammatory diseases. The eye is uniquely sensitive to the TLR4 agonist, LPS, and LPS-induced uveitis has been well-established in various rodent models. How activation of other TLRs may influence the onset and/or severity of uveitis has not been thoroughly examined. Here, we systematically examined the inflammatory potential of 9 TLRs (TLR1/2, TLR2/6, TLR3, TLR4, TLR5, TLR7/8, and TLR9) for their ability to trigger uveitis in mice.
Female, age-matched BALB/c mice were administered intravitreal injections of the following synthetic TLR agonists: Pam3CSK4 (TLR2/1), FSL-1 (TLR2/6), Poly(I:C) (TLR3), lipid A (TLR4), flagellin (TLR5), R848 (TLR7/8) and CpG ODN (TLR9). The contralateral eye was intravitreally injected with saline or appropriate peptide or nucleic acid controls. The leukocytic response within the vasculature and extravascular tissue of the iris was assessed using intravital videomicroscopy over the first 24 h following injections. The inflammatory potential of TLR agonists was also assessed in iris or retina explant cultures. Cytokine production within the supernatants was then quantified by Luminex-ELISA at 24 h post stimulation.
Iris or retina explants directly stimulated with various TLR agonists demonstrated marked increase in production of inflammatory cytokines (IL-6, IP-10/CXCL10, KC, MCP-1, and RANTES) but relatively little production of IFNγ, IL-12p70, IL-10, IL-1β, IL-4 or TNFα). Some unique cytokine profiles were noted. For example Poly(I:C) (TLR3 agonist) triggered greater amounts of IP-10 production compared to TLR2 agonists (Pam3CSK4 or FSL1). Overall, iris tissue was more sensitive to TLR stimulation than retina tissue. Despite the ability of all TLR agonists tested to elicit cytokine production in iris explants, the inflammatory potential of TLR agonists differed greatly when administered locally to the eye. For example, Poly(I:C) (TLR3 agonist) was a very poor trigger of uveitis compared to CpG ODN (TLR9 agonist), lipid A (TLR4 agonist) or TLR2 agonists.
Our data provide insight into how activation of different TLRs may predispose to uveitis in mice. Intriguingly, despite comparable TLR-triggered cytokine production in vitro, the in vivo responses were more variable.
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