1.3 - LXA4 and bacterial infections
Various studies suggest that LXA4 plays a protective role in models of pulmonary infection by Pseudomonas aeruginosa (P. aureoginosa ). Treatment with LXA4 was found to decrease bacterial proliferation and increase the efficacy of antibiotics against P. aeruginosa biofilms (Wu et al, 2016; Thornton et al, 2021). LXA4 also prevented P. aeruginosa invasion by preventing tight junction disruption and stimulating the protein levels of ZO-1 in cultured airway epithelial cells obtained from patients with cystic fibrosis (Higgins et al, 2016). The significance of LXA4 for these bacteria can be highlighted by the ability of P. aeruginosa to develop mechanisms to sabotage the lipoxin system. These bacteria may secrete an epoxide hydrolase called conductance regulator inhibitor (Cif), which disrupts the synthesis of 15-Epi-LXA4 by host cells. In the BAL fluid of cystic fibrosis patients, increased levels of Cif were associated with decreased levels of LXA4, augmented concentration of IL-8, and impaired lung function (Flitter et al, 2017). The epoxide hydrolase secreted by these bacteria also decreased mucociliary transport and hindered bacterial clearance from the lung (Hvorecny et al, 2018). These findings provide compelling evidence that LXA4 contributes to bacterial clearance and host protection during P. aeruginosa infection, both in pre-clinical models and in humans.
LXA4 has also been found to have beneficial effects duringPorphyromonas gingivalis (P. gingivalis ) infection. LXA4 was shown to decrease the activation of integrin CD11b/CD18, reduce ROS generation in whole blood, inhibit cell activation, and prevent P. gingivalis aggregation. In a model of periodontitis induced by P. gingivalis , treatment with a stable analog of LXA4 limited neutrophil recruitment and tissue injury in the oral cavity (Börgeson et al, 2011). Additionally, both human neutrophils exposed to P. gingivalis and a mouse model showed increased COX-2 levels, which were decreased with LXA4 treatment (Pouliot et al, 2000). Furthermore, LXA4 was found to promote autophagy and inhibit the inflammasome in RAW264.7 cells exposed to P. gingivalis lipopolysaccharide (PgLPS) (Zhao et al, 2021).
Treatment of mice with 15-Epi-LXA4 during peak lung inflammation led to the clearance of Escherichia coli (E. coli ) and promoted neutrophil apoptosis and efferocytosis (Sekheri et al, 2020). Treatment was effective in reducing the levels of IL-6 and TNF when administered in combination with antibiotics (Ueda et al, 2014). Other studies have also shown the potential therapeutic benefits of LXA4 during lung inflammation (Wu et al, 2014). During UV-killed E. coli exposure in human skin, LXA4 and other SPMs were synthesized in a time-dependent manner, which coincided with the expression of the FPR2 receptor and the start of the resolution phase (Motwani et al, 2018). Additionally, stable analogs of LXA4 demonstrated beneficial effects in treatingSalmonella typhimurium (S. typhimurium) infection, pneumococcal pneumonia, LPS-induced lung injury, and cecal ligation and puncture (CLP) in a rat model (see Supplementary Table 1) (Gewirtz et al, 1998; Siegel et al, 2021; Qi et al, 2015; Walker et al, 2011; Wu et al, 2014).
However, in the case of Klebsiella pneumoniae (K. pneumoniae) pneumosepsis in mice, levels of LXA4 were increased in the early stage of sepsis and were associated with local and systemic infection, leading to high mortality rates. Treatment with LXA4 during early sepsis worsened the infection, while late treatment improved survival by reducing excessive inflammation (Sordi et al, 2013). Moreover, our research group showed that LXA4 treatment hindered the migration of dendritic cells in the joint during Staphylococcus aureus (S. aureus ) infection, which was crucial in reducing bacterial burden (Boff et al, 2020). Overall, these findings suggest that the development of lipoxin-based therapies may not be straightforward, as the type of bacteria and the timing of therapy initiation may significantly impact the effectiveness of LXA4 or its analogues.