期刊
FRONTIERS IN IMMUNOLOGY
卷 12, 期 -, 页码 -出版社
FRONTIERS MEDIA SA
DOI: 10.3389/fimmu.2021.553911
关键词
sepsis; host-pathogen interactions; peritonitis; Candida albicans; inflammation; A9 complex; host-targeted agents
类别
资金
- Swedish research council [VR-M 2014-02281, VR-M 2017-01681]
- Kempe Foundation [SMK-1453]
- Ake Wiberg Foundation [M14-0076, M15-0108]
- Medical Faculty of Umea University [316-886-10]
- UCMR
- Interdisciplinary Center of Clinical Research at the University of Munster [Ro2/023/19, Vo2/011/19]
- German Research Foundation [CRC 1009]
S100A8/A9 protein complex plays a critical role in inflammatory collateral tissue damage, with its deficiency reducing tissue injury and increasing fungal clearance. Restoring S100A8/A9 levels can increase tissue damage and fungal clearance, indicating that targeting S100A8/A9 could serve as a promising adjunct therapy against challenging intra-abdominal infections.
Intra-abdominal infection (peritonitis) is a leading cause of severe disease in surgical intensive care units, as over 70% of patients diagnosed with peritonitis develop septic shock. A critical role of the immune system is to return to homeostasis after combating infection. S100A8/A9 (calprotectin) is an antimicrobial and pro-inflammatory protein complex used as a biomarker for diagnosis of numerous inflammatory disorders. Here we describe the role of S100A8/A9 in inflammatory collateral tissue damage (ICTD). Using a mouse model of disseminated intra-abdominal candidiasis (IAC) in wild-type and S100A8/A9-deficient mice in the presence or absence of S100A9 inhibitor paquinimod, the role of S100A8/A9 during ICTD and fungal clearance were investigated. S100A8/A9-deficient mice developed less ICTD than wild-type mice. Restoration of S100A8/A9 in knockout mice by injection of recombinant protein resulted in increased ICTD and fungal clearance comparable to wild-type levels. Treatment with paquinimod abolished ICTD and S100A9-deficient mice showed increased survival compared to wild-type littermates. The data indicates that S100A8/A9 controls ICTD levels and antimicrobial activity during IAC and that targeting of S100A8/A9 could serve as promising adjunct therapy against this challenging disease.
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