Abstract
BackgroundEndophthalmitis is a serious intraocular infection that frequently results in significant inflammation and vision loss. Because current therapeutics are often unsuccessful in mitigating damaging inflammation during endophthalmitis, more rational targets are needed. Toll-like receptors (TLRs) recognize specific motifs on invading pathogens and initiate the innate inflammatory response. We reported that TLR4 contributes to the robust inflammation which is a hallmark of Bacillus cereus endophthalmitis. To identify novel, targetable host inflammatory factors in this disease, we performed microarray analysis to detect TLR4-dependent changes to the retinal transcriptome during B. cereus endophthalmitis.ResultsC57BL/6 J and TLR4−/− mouse eyes were infected with B. cereus and retinas were harvested at 4 h postinfection, a time representing the earliest onset of neutrophil infiltration. Genes related to acute inflammation and inflammatory cell recruitment including CXCL1 (KC), CXCL2 (MIP2-α), CXCL10 (IP-10), CCL2 (MCP1), and CCL3 (MIP1-α)) were significantly upregulated 5-fold or greater in C57BL/6 J retinas. The immune modulator IL-6, intercellular adhesion molecule ICAM1, and the inhibitor of cytokine signal transduction SOCS3 were upregulated 25-, 11-, and 10-fold, respectively, in these retinas. LIF, which is crucial for photoreceptor cell survival, was increased 6-fold. PTGS2/COX-2, which converts arachidonic acid to prostaglandin endoperoxide H2, was upregulated 9-fold. PTX3, typically produced in response to TLR engagement, was induced 15-fold. None of the aforementioned genes were upregulated in TLR4−/− retinas following B. cereus infection.ConclusionsOur results have identified a cohort of mediators driven by TLR4 that may be important in regulating pro-inflammatory and protective pathways in the retina in response to B. cereus intraocular infection. This supports the prospect that blocking the activation of TLR-based pathways might serve as alternative targets for Gram-positive and Gram-negative endophthalmitis therapies in general.
Highlights
Endophthalmitis is a serious intraocular infection that frequently results in significant inflammation and vision loss
Endophthalmitis is a serious infection of the posterior segment of the eye which occurs from introduction of microbes following a surgical procedure, a traumatic penetrating injury, or bloodstream spread from an infection of a distant site in the body
The expression of 14 out of 15 of these genes was found to be unaltered in TLR4−/− mice relative to uninfected controls, indicating their dependency on TLR4 (Table 1). These genes included key mediators in neutrophil recruitment, and activation of photoreceptor survival and pathogen clearance mechanisms in response to B. cereus infection. These results further suggest that the TLR4 pathway might serve as a target for new anti-inflammatory treatments critically needed to control the explosive inflammation seen in B. cereus ocular infection, and ocular infections due to Klebsiella pneumoniae and other Gram negative pathogens
Summary
Endophthalmitis is a serious intraocular infection that frequently results in significant inflammation and vision loss. Targetable host inflammatory factors in this disease, we performed microarray analysis to detect TLR4-dependent changes to the retinal transcriptome during B. cereus endophthalmitis. Results: C57BL/6 J and TLR4−/− mouse eyes were infected with B. cereus and retinas were harvested at 4 h postinfection, a time representing the earliest onset of neutrophil infiltration. Genes related to acute inflammation and inflammatory cell recruitment including CXCL1 (KC), CXCL2 (MIP2-α), CXCL10 (IP-10), CCL2 (MCP1), and CCL3 (MIP1-α)) were significantly upregulated 5-fold or greater in C57BL/6 J retinas. None of the aforementioned genes were upregulated in TLR4−/− retinas following B. cereus infection. There is currently no universal therapeutic regimen which prevents the significant inflammation and vision loss associated with severe forms of endophthalmitis.
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