Abstract
Sterile inflammation underlies many diseases of the cornea including serious chemical burns and the common dry eye syndrome. In search for therapeutic targets for corneal inflammation, we defined the kinetics of neutrophil infiltration in a model of sterile injury to the cornea and identified molecular and cellular mechanisms triggering inflammatory responses. Neutrophil infiltration occurred in two phases: a small initial phase (Phase I) that began within 15 min after injury, and a larger second phase (Phase II) that peaked at 24–48 h. Temporal analysis suggested that the neuropeptide secretoneurin initiated Phase I without involvement of resident macrophages. Phase II was initiated by the small heat shock protein HSPB4 that was released from injured keratocytes and that activated resident macrophages via the TLR2/NF-κB pathway. The Phase II inflammation was responsible for vision-threatening opacity and was markedly suppressed by different means of inhibition of the HSPB4/TLR2/NF-κB axis: in mice lacking HSPB4 or TLR2, by antibodies to HSPB4 or by TNF-α stimulated gene/protein 6 that CD44-dependently inhibits the TLR2/NF-κB pathway. Therefore, our data identified the HSPB4/TLR2/NF-κB axis in macrophages as an effective target for therapy of corneal inflammation.
Highlights
Sterile inflammation is recognized to play a key role in many diseases that include myocardial infarction, stroke, Alzheimer’s disease and atherosclerosis (Chen & Nunez, 2010; Rock et al, 2010; Spite & Serhan, 2010)
Neutrophil infiltration occurred in two phases: a small initial phase (Phase I) that began within 15 min after injury, and a larger second phase (Phase II) that peaked at 24–48 h
In search for the stimuli for Phase I and II responses, we screened for the molecules upregulated in the cornea in each phase after an injury on the assumption that the molecules produced actively by tissues in response to an injury might act as the major stimuli to initiate the sterile inflammation
Summary
Sterile inflammation is recognized to play a key role in many diseases that include myocardial infarction, stroke, Alzheimer’s disease and atherosclerosis (Chen & Nunez, 2010; Rock et al, 2010; Spite & Serhan, 2010). The molecular and cellular responses of sterile inflammation include over 20 nonmicrobial endogenous stimuli referred to as damageassociated molecular patterns (DAMPs). To identify therapeutic targets, it is probably essential to identify the major DAMP or DAMPs that play essential roles in initiating sterile inflammation in a specific disease and tissue. To search for novel therapeutic targets for sterile inflammation, we adopted a model of chemical and mechanical injury in which the cornea was injured by exposure to ethanol and mechanical scraping to remove both the epithelium www.embomolmed.org
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