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.