Corneal epithelial injury-induced norepinephrine promotes Pseudomonas aeruginosa keratitis.

Tissue injury causes the secretion of stress hormone catecholamine and increases susceptibility to opportunistic infection. Pseudomonas aeruginosa (P. aeruginosa) is an opportunistic pathogen that is a leading cause of microbial keratitis usually associated with ocular injury or contact lens wear. However, the effect of catecholamine on P. aeruginosa induced corneal infection is unknown. Here, we test if norepinephrine (NE) would promote the progression of P. aeruginosa keratitis in mice. Adult C57BL/6 mouse corneas were scarified and then inoculated with P. aeruginosa. The content of NE was elevated in corneas after scarification and inoculation with P. aeruginosa. Then, exogenous NE was applied to the infected corneas at 24 h after inoculation; control eyes were treated with sterile saline. Topical application of NE aggravated the severity of P. aeruginosa keratitis, accompanied with the increase of clinical score, bacterial load, pathological changes, neutrophils infiltration, bacterial virulence factors and proinflammatory factors levels. In order to further verify the role of NE, N-(2-Chloroethyl)-N-ethyl-2-bromobenzylamine hydrochloride (DSP-4), a neurotoxin selected to deplete NE, was injected subconjunctivally 12 h before scarification. Pre-depletion of local NE by DSP-4 significantly alleviated the severity of corneal infection. Moreover, NE was also confirmed to increase the bacterial growth and the expression of virulence factors gene in vitro. Together, these data showed that increased corneal NE content facilitated the progression of P. aeruginosa keratitis in mice by amplifying host excessive inflammatory response and bacterial virulence. Therefore, targeting NE may provide a potential strategy for the treatment of P. aeruginosa keratitis.