Bacterial keratitis (BK) is an ophthalmic emergency and a major cause of blindness globally. Gram-positive and gram-negative bacilli are the main pathogenic bacteria responsible for BK, among which Pseudomonas aeruginosa (PA) is the most prevalent gram-negative pathogen (Stapleton, 2021). Pseudomonas aeruginosa often induces excessive inflammatory responses, which may lead to corneal scarring or perforation (Hazlett, 2004). During these inflammatory responses, macrophages act as immunomodulatory cells that modulate their phenotype in response to the local microenvironment. Macrophages are mainly divided into two subsets: M1 (pro-inflammatory) macrophages, which are characterized by the production of inducible nitric oxide synthase (iNOS or NOS2), and M2 macrophages (anti-inflammatory), characterized by the production of arginase 1 (Arg-1) (Edwards et al., 2006, Mantovani et al., 2002, Mills et al., 2000). Anti-inflammatory drugs are beneficial for improving the prognosis of PA keratitis (Austin et al., 2017, Thakur et al., 2004, Yerramothu et al., 2018). Furthermore, shifting macrophages toward the M2 phenotype can alleviate corneal inflammation owing to their anti-inflammatory properties (Hazlett et al., 2010, Zhu et al., 2021).

Resolvins are endogenously secreted mediators of inflammation resolution (Schwab et al., 2007), and those derived from docosahexaenoic acid (DHA) are known as resolvin D (RvD) (Kohli and Levy, 2009). The receptors of RvD1 include lipoxin A4 receptor (ALX)/ formyl peptide receptor-2 (FPR2) and G protein-coupled receptor-32 (Krishnamoorthy et al., 2010, Serhan et al., 2002). ALX/FPR2 is expressed in corneal epithelial cells (Bu et al., 2019, He et al., 2011, Hua et al., 2014, Jin et al., 2009), and its activation promotes the resolution of inflammation in keratitis (Carion et al., 2019, Petrillo et al., 2020). An in vitro study confirmed that RvD1 treatment inhibits the secretion of TNF-α, IL-6, and IL-8 in human corneal epithelial cells, similar to dexamethasone (Erdinest et al., 2014). Another in vivo study showed that RvD1 could promote the polarization of M2 macrophages through the IL-10 pathway in lipopolysaccharide (LPS)-induced keratitis (Petrillo et al., 2020). RvD1 can also protect against inflammatory responses induced by herpes simplex keratitis (HSK) (Rajasagi et al., 2017). These findings suggest that RvD1 acts as an immune modulator and may also be involved in the inflammatory response during macrophage polarization in BK. However, the importance of RvD1 in the inflammatory response of macrophages infected with PA in the cornea has not yet been clarified. Considering that the biosynthesis of RvD1 in inflammatory tissues is transient owing to its degradation (Chiang et al., 2012), elucidating the effects of exogenous RvD1 may create a new effective therapeutic approach for PA keratitis. In this study, we aimed to explore the protective effects of RvD1 in PA keratitis using a mouse model.