Annexin A1 Attenuates Neutrophil Migration and IL-6 Expression through Fpr2 in a Mouse Model of Streptococcus suis-Induced Meningitis

Abstract

Streptococcus suis (S. suis) serotype 2 is a crucial pathogenic cause of bacterial meningitis, a life-threatening disease with neurological sequelae and high rates of mortality. Inflammation triggered by S. suis infection must be precisely regulated to prevent further tissue damage. As a glucocorticoid anti-inflammatory mediator, Annexin A1 (AnxA1) mainly acts through formyl peptide receptor 2 (Fpr2) to alleviate inflammation in the peripheral system. In this research, we evaluated the roles of AnxA1 and Fpr2 in a mouse model of S. suis meningitis created via intracisternal infection in Fpr2-deficient (Fpr2−/−) and wild-type (WT) mice. We revealed that Fpr2−/− mice were highly susceptible to S. suis meningitis, displaying increased inflammatory cytokine levels, bacterial dissemination, and neutrophil migration compared with the findings in WT mice. Additionally, AnxA1 exerted anti-inflammatory effects through Fpr2, such as attenuation of leukocyte infiltration, inflammatory mediator production, and astrocyte or microglial activation in the brain. Importantly, we found that the anti-migratory function of AnxA1 decreases neutrophil adherence to the endothelium through Fpr2. Finally, an in vitro study revealed that AnxA1 potentially suppresses IL-6 expression through the Fpr2/p38/COX-2 pathway. These data demonstrated that Fpr2 is an anti-inflammatory receptor that regulates neutrophil migration in mice with S. suis meningitis and identified AnxA1 as a potential therapeutic option.

Formyl Peptide Receptor (FPR)1 Modulation by Resveratrol in an LPS-Induced Neuroinflammatory Animal Model

“…Studies on mouse models of bacterial meningitis revealed a stronger glial cell marker expression in FPR1-deficient mice and an increase of activated microglial cells and neutrophil infiltration in FPR1- or FPR2-deficient mice, thus suggesting that FPRs exert an important role in the immune responses within the CNS and that the lack of these receptors leads to a dysregulation of the inflammatory response compared with wild-type mice. In this context, these researchers have observed that the proinflammatory reactions in FPR1 and FPR2 deficient cells resulted significantly increased [ 10 , 45 ]. Moreover, it has been demonstrated that FPRs play a major role in crotoxin anti-inflammatory activities that are inhibited by the pretreatment with Boc2, a selective antagonist of FPRs [ 46 , 47 ].…”

The Role of Formyl Peptide Receptors in Neurological Diseases via Regulating Inflammation

“…Another study using a mouse model of Streptococcus suis -induced meningitis, indicated that AnxA1 exerted anti-inflammatory effects via attenuating leukocyte infiltration, inflammatory mediator production, and astrocyte or microglial activation in the brain, along with decreasing neutrophil adherence to the endothelium through FPR2, thus inhibiting meningitis progression. Significantly, the study also revealed that AnxA1 decreases IL-6 expression and effect through the FPR2/p38/COX-2 pathway ( Ni et al, 2021 ). These data highlight the potential therapeutic use of AnxA1 in bacterial meningitis.…”

Neutrophils in Streptococcus suis Infection: From Host Defense to Pathology

“…Among the 46 articles studying in vitro activation of neutrophils by S. suis, only 13 studies (28%) measured neutrophil purity after isolation [44,45,54,62,[69][70][71][72][73][74][75][76][77] (Figure 3). A diversity of methods were used to assess cell purity: Giemsa/Wright's stain [44,73,74], Hoechst stain (microscopy) [71,72] or flow cytometry using different markers (for exam-ple, Ly6G+, CD11b+) [54,[75][76][77]. However, in these studies, the purity was comprised between 75% and 97% and the high risk of contaminating cells probably compromised the interpretation of the results when the purity was low.…”