Telomere Dysfunction Disturbs Macrophage Mitochondrial Metabolism and the NLRP3 Inflammasome through the PGC-1α/TNFAIP3 Axis

Publication date: 27 March 2018
Source:Cell Reports, Volume 22, Issue 13
Author(s): Yanhua Kang, Hang Zhang, Yufang Zhao, Yan Wang, Wei Wang, Yan He, Wei Zhang, Weiwei Zhang, Xudong Zhu, Yong Zhou, Lingling Zhang, Zhenyu Ju, Liyun Shi
Immune and inflammation dysregulation have been associated with the aging process and contribute to age-related disorders, but the underlying mechanism remains elusive. Here, we employed late-generation Terc knockout (Terc^−/−) mice to investigate the impact of telomere dysfunction on the host defense and function of innate immune cells. Terc^−/− mice displayed exaggerated lung inflammation and increased mortality upon respiratory staphylococcal infection, although their pathogen-clearing capacity was uncompromised. Mechanistically, we found that telomere dysfunction caused macrophage mitochondrial abnormality, oxidative stress, and hyperactivation of the NLRP3 inflammasome. The ubiquitin-editing enzyme TNFAIP3, together with PGC-1α, was critically involved in the regulation of mitochondrial and inflammatory gene expression and essential for the homeostatic role of telomeres. Together, the study reveals a regulatory paradigm that connects telomeres to mitochondrial metabolism, innate immunity, and inflammation, shedding light on age-related pathologies.

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Teaser

Kang et al. show that dysfunctional telomeres cause macrophage mitochondrial distress, metabolic imbalance, and hyperactivation of the NLRP3 inflammasome. They identify the PGC1α/TNFAIP3 axis as a mechanism responsible for the homeostatic role of the telomere, the disturbance of which leads to inflammatory Terc^−/− macrophages and severe bacterial pneumonia in Terc^−/− mice.


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