期刊
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
卷 106, 期 26, 页码 10740-10745出版社
NATL ACAD SCIENCES
DOI: 10.1073/pnas.0904412106
关键词
Akt phosphorylation; CTMP; innate immunity; iNOS; TLR2
资金
- National Institute of Dental and Craniofacial Research [DE15989]
Recent research links diet-induced obesity (DIO) with impaired immunity, although the underlying mechanisms remain unclear. We find that the induction of inducible NO synthase (iNOS) and cytokines is suppressed in mice with DIO and in bone marrow macrophages (BMM Phi) from mice with DIO exposed to an oral pathogen, Porphyromonas gingivalis. BMM Phi from lean mice pre-treated with free fatty acids (FFAs) and exposed to P. gingivalis also exhibit a diminished induction of iNOS and cytokines. BMM Phi from lean and obese mice exposed to P. gingivalis and analyzed by a phosphorylation protein array show a reduction of Akt only in BMM Phi from mice with DIO. This reduction is responsible for diminished NF-kappa B activation and diminished induction of iNOS and cytokines. We next observed that Toll-like receptor 2 (TLR2) is suppressed in BMM Phi from DIO mice whereas carboxy-terminal modulator protein (CTMP), a known suppressor of Akt phosphorylation, is elevated. This elevation stems from defective TLR2 signaling. In BMM Phi from lean mice, both FFAs and TNF-alpha-via separate pathways-induce an increase in CMTP. However, in BMM Phi from DIO mice, TLR2 can no longer inhibit the TNF-alpha-induced increase in CTMP caused by P. gingivalis challenge. This defect can then be restored by transfecting WT TLR2 into BMM Phi from DIO mice. Thus, feeding mice a high-fat diet over time elevates the CTMP intracellular pool, initially via FFAs activating TLR2 and later when the defective TLR2 is unable to inhibit TNF-alpha-induced CTMP. These findings unveil a link between obesity and innate immunity.
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