Xi Huang
Zhongshan School of Medicine， Sun Yat-sen University
Toll-like receptor/interleukin-1 receptor (TLR/IL-1R) family of molecules provide a first line of host defense by recognizing conserved microbial components (e.g.， endotoxin LPS)， activating signaling cascades， and initiating innate immunity. Members of the TLR superfamily such as TLR4， TLR9 also participate in regulation of inflammatory angiogenesis， apoptosis and acquired immune responses. Recently， a novel subfamily of negative regulators， single immunoglobulin IL-1R-related molecule (SIGIRR) and ST2 have been shown to negatively regulate TLR-driven inflammatory responses and to modulate Th1/Th2 bias. It is unknown whether SIGIRR and/or ST2 regulates keratitis induced by Pseudomonas aeruginosa (P. aeruginosa)， that causes corneal perforation in dominant Th1 type susceptible mouse strains such as C57BL/6 (B6)， while Th2 dominant strains such as BALB/c (resistant)， clear the infection. To elucidate the role of TLRs and their negative regulators in susceptible vs. resistance to P. aeruginosa keratitis， multiple approaches have been used to test TLR expression， distribution， signaling， and immunoregulatory properties. The hypothesis to be tested is that TLRs (e.g.， TLR-4， TLR-9) and their negative regulators (e.g.， SIGIRR， ST2) play a critical role in the innate immune response in the cornea and are responsible for the disparate outcome to P. aeruginosa infection of B6 and BALB/c mice. By integrating cellular and molecular biology and immunology， we have elucidated the role of the TLR superfamily members in the innate and adaptive immune response to experimental P. aeruginosa corneal infection resulting in corneal perforation (B6) vs. healing (BALB/c). Our long-term Objective is to reveal basic pathophysiological mechanisms of disease in the P. aeruginosa infected cornea. It is expected that our findings will be significant to treatment of P. aeruginosa keratitis， providing potential targets for early therapeutic intervention.
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