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  • RIP3-mediated necrotic cell death accelerates systematic inflammation and mortality.

RIP3-mediated necrotic cell death accelerates systematic inflammation and mortality.

Proceedings of the National Academy of Sciences of the United States of America (2015-08-19)
Lingjun Meng, Wei Jin, Xiaodong Wang
ABSTRACT

Systematic inflammation contributes to the development of many diseases, including cardiovascular disease, which is the leading cause of mortality worldwide. How such inflammation is initiated and maintained throughout the course of disease remains unclear. In the current study, we report the observation of specific phosphorylation of the receptor-interacting protein 3 (RIP3) kinase that marks the activation of programmed necrosis (also called the "necroptosis pathway") in the atherosclerotic plaques in apolipoprotein E (ApoE)-knockout mice. The mRNA expression levels of 10 inflammatory cytokines, including IL-1α, were decreased significantly in the plaque regions of mice lacking RIP3. Lymphocyte infiltrations in the adipocyte tissue and in skin lesions of ApoE single-knockout mice were significantly mitigated in ApoE/RIP3 double-knockout mice. The high percentage of inflammatory monocytes with high levels of lymphocyte antigen 6C in the blood of ApoE single-knockout mice also was greatly decreased in the ApoE/RIP3 double-knockout mice. Most significantly, the double-knockout mice displayed dramatically delayed mortality compared with ApoE single-knockout mice. Our findings indicate that necrotic death in areas such as atherosclerotic plaques may release cytokines that mobilize monocytes from bone marrow to the lesion sites, exacerbating the lesions in multiple tissues and resulting in the premature death of the animals.

MATERIALS
Product Number
Brand
Product Description

Sigma-Aldrich
Polyinosinic–polycytidylic acid potassium salt, γ-irradiated
Sigma-Aldrich
Polyinosinic–polycytidylic acid potassium salt, with buffer salts, TLR ligand tested
Sigma-Aldrich
Lipopolysaccharides from Escherichia coli O111:B4, purified by gel-filtration chromatography
Sigma-Aldrich
Triton X-100, laboratory grade