期刊
ARTERIOSCLEROSIS THROMBOSIS AND VASCULAR BIOLOGY
卷 40, 期 9, 页码 2279-2292出版社
LIPPINCOTT WILLIAMS & WILKINS
DOI: 10.1161/ATVBAHA.120.314491
关键词
extracellular traps; interferons; lipopolysaccharide; neutrophils; venules
资金
- intramural MAIFOR (Mainzer Forschungsprotramm) grant
- Inneruniversitare Forschungsforderung (Stufe 1)
- CTH (Center for Thrombosis and Hemostasis) Junior Group Translational Research in Thrombosis and Hemostasis (BMBF [Bundesministerium fur Bildung und Forschung]) [01EO1003, 01EO1503]
- DFG (Deutsche Forschungsgemeinschaft) [RE 3450/3-1, RE 3450/5-1, RE 3450/5-2 BO 3482/3-3, BO 3482/4-1]
- National Institutes of Health [1R01HL141513, 1R01HL139641]
- NaturwissenschaflichMedizinisches Forschungszentrum at the Johennes Gutenberg University of Mainz (NMFZ)
- Boehringer Ingelheim Foundation (Novel and neglected cardiovascular risk factors)
Objective: Recruitment of neutrophils and formation of neutrophil extracellular traps (NETs) contribute to lethality in acute mesenteric infarction. To study the impact of the gut microbiota in acute mesenteric infarction, we used gnotobiotic mouse models to investigate whether gut commensals prime the reactivity of neutrophils towards formation of neutrophil extracellular traps (NETosis). Approach and Results: We applied a mesenteric ischemia-reperfusion (I/R) injury model to germ-free (GF) and colonized C57BL/6J mice. By intravital imaging, we quantified leukocyte adherence and NET formation in I/R-injured mesenteric venules. Colonization with gut microbiota or monocolonization withEscherichia coliaugmented the adhesion of leukocytes, which was dependent on the TLR4 (Toll-like receptor-4)/TRIF (TIR-domain-containing adapter-inducing interferon-beta) pathway. Although neutrophil accumulation was decreased in I/R-injured venules of GF mice, NETosis following I/R injury was significantly enhanced compared with conventionally raised mice or mice colonized with the minimal microbial consortium altered Schaedler flora. Also ex vivo, neutrophils from GF and antibiotic-treated mice showed increased LPS (lipopolysaccharide)-induced NETosis. Enhanced TLR4 signaling in GF neutrophils was due to elevated TLR4 expression and augmented IRF3 (interferon regulatory factor-3) phosphorylation. Likewise, neutrophils from antibiotic-treated conventionally raised mice had increased NET formation before and after ischemia. Increased NETosis in I/R injury was abolished in conventionally raised mice deficient in the TLR adaptor TRIF. In support of the desensitizing influence of enteric LPS, treatment of GF mice with LPS via drinking water diminished LPS-induced NETosis in vitro and in the mesenteric I/R injury model. Conclusions: Collectively, our results identified that the gut microbiota suppresses NETing neutrophil hyperreactivity in mesenteric I/R injury, while ensuring immunovigilance by enhancing neutrophil recruitment.
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