Interleukin-33 Increases Antibacterial Defense by Activation of Inducible Nitric Oxide Synthase in Skin

PLoS Pathogens

Zhaofan Xia¹  Shizhao Ji¹  Shichu Xiao¹  Bernhard Ryffel²  Katherine A. Radek³  Tian Zhang⁴  Changwei Li⁴  Yuping Lai⁴  Zhiheng Li⁴  Hongquan Li⁴  Yelin Wu⁴  Yue Wang⁴  Ziwei Jiang⁴ 

[1] Burn Institute of Chinese PLA and Department of Burn Surgery, Changhai Hospital, Second Military Medical University, Shanghai, China;CNRS, UMR7355, University of Orleans, Orleans, France;Department of Surgery, Burn and Shock Trauma Research Institute, Loyola University Chicago, Health Sciences Campus, Maywood, Illinois, United States of America;Shanghai Key Laboratory of Regulatory Biology, School of Life Sciences, East China Normal University, Shanghai, China

关键词: Macrophages;    Skin infections;    Staphylococcus aureus;    Neutrophils;    Staphylococcal infection;    Toll-like receptors;    Keratinocytes;    Lesions;   

DOI  :  10.1371/journal.ppat.1003918

学科分类：生物科学（综合）

来源: Public Library of Science

【 摘 要 】

Interleukin-33 (IL-33) is associated with multiple diseases, including asthma, rheumatoid arthritis, tissue injuries and infections. Although IL-33 has been indicated to be involved in Staphylococcus aureus (S. aureus) wound infection, little is known about how IL-33 is regulated as a mechanism to increase host defense against skin bacterial infections. To explore the underlying intricate mechanism we first evaluated the expression of IL-33 in skin from S. aureus-infected human patients. Compared to normal controls, IL-33 was abundantly increased in skin of S. aureus-infected patients. We next developed a S. aureus cutaneous infection mouse model and found that IL-33 was significantly increased in dermal macrophages of infected mouse skin. The expression of IL-33 by macrophages was induced by staphylococcal peptidoglycan (PGN) and lipoteichoic acid (LTA) via activation of toll-like receptor 2(TLR2) –mitogen-activated protein kinase (MAPK)-AKT-signal transducer and activator of transcription 3(STAT3) signaling pathway as PGN and LTA failed to induce IL-33 in Tlr2-deficient peritoneal macrophages, and MAPK,AKT, STAT3 inhibitors significantly decreased PGN- or LTA-induced IL-33. IL-33, in turn, acted on macrophages to induce microbicidal nitric oxygen (NO) release. This induction was dependent on inducible nitric oxide synthase (iNOS) activation, as treatment of macrophages with an inhibitor of iNOS, aminoguanidine, significantly decreased IL-33-induced NO release. Moreover, aminoguanidine significantly blocked the capacity of IL-33 to inhibit the growth of S. aureus, and IL-33 silencing in macrophages significantly increased the survival of S. aureus in macrophages. Furthermore, the administration of IL-33-neutralizing antibody into mouse skin decreased iNOS production but increased the survival of S. aureus in skin. These findings reveal that IL-33 can promote antimicrobial capacity of dermal macrophages, thus enhancing antimicrobial defense against skin bacterial infections.

【 授权许可】

CC BY