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

Chengpei Ni,Wenhua Huang,Yongqiang Jiang,Song Gao,Yuling Zheng,Qingyu Lv,Yajie Zhai,Decong Kong,Hua Jiang,Peng Liu,Guy H Palmer

doi:10.1128/iai.00680-20

Chengpei Ni, Wenhua Huang + Show 9 more

Open Access

https://doi.org/10.1128/iai.00680-20

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Abstract

Streptococcus 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 study, 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 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 antimigratory function of AnxA1 decreases neutrophil adherence to the endothelium through Fpr2. Finally, an in vitro study revealed that AnxA1 potentially suppresses interleukin-6 (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.

Highlights

Streptococcus suis serotype 2 is a crucial pathogenic cause of bacterial meningitis, a life-threatening disease with neurological sequelae and high rates of mortality
These results indicated the protective function of formyl peptide receptor 2 (Fpr2) during S. suis meningitis
In this study, we uncovered that the lack of Fpr2 exacerbated S. suis-induced meningitis in mice infected with the Chinese virulent strain 05ZYH33, and annexin A1 (AnxA1) administration exerted anti-inflammatory effects through Fpr2 in S. suis-infected mice

Summary

Introduction

Streptococcus suis serotype 2 is a crucial pathogenic cause of bacterial meningitis, a life-threatening disease with neurological sequelae and high rates of mortality. AnxA1 exerted anti-inflammatory effects through Fpr, such as attenuation of leukocyte infiltration, inflammatory mediator production, and astrocyte or microglial activation in the brain. An in vitro study revealed that AnxA1 potentially suppresses interleukin-6 (IL-6) expression through the Fpr2/p38/COX-2 pathway. These data demonstrated that Fpr is an anti-inflammatory receptor that regulates neutrophil migration in mice with S. suis meningitis and identified AnxA1 as a potential therapeutic option. Streptococcus suis is a crucial swine and human pathogen responsible for sudden death, septic shock, and meningitis, which are characterized by exacerbated inflammation in both systemic and central nervous system (CNS) infections [1, 2]. The protein modulates the induction of proinflammatory mediators, including those derived from the activation of PLA2, cyclooxygenase-2 (COX-2), and inducible nitric oxide synthase [11,12,13]

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