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Summary: The increasing rising of multiple drug-resistant Staphylococcus aureus has become a major public health concern, underscoring a pressing need for developing therapies essentially based on the understanding of host defensive mechanism. In the present study, we showed that microRNA (miR)-127 played a key role in controlling bacterial infection and conferred a profound protection against staphylococcal pneumonia. The protective effect of miR-127 was largely dependent on its regulation of macrophage bactericidal activity and the generation of IL-22, IL-17, and anti-microbial peptides (AMPs), the pathway primarily driven by STAT3. Importantly, we revealed that the ubiquitin-editing enzyme A20, a genuine target of miR-127, specifically interacted with and repressed K63-ubiquitination of STAT3, thereby compromising its phosphorylation upon bacterial infection. Thus, our data not only identify miR-127 as a non-coding molecule with anti-bacterial activity but also delineate an unappreciated mechanism whereby A20 regulates STAT3-driven anti-microbial signaling via modulating its ubiquitination. : Molecular Mechanism of Behavior; Immunology; Microbiology; Bacteriology Subject Areas: Molecular Mechanism of Behavior, Immunology, Microbiology, Bacteriology

Summary: 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. : 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. Keywords: telomere, macrophages, inflammasome, mitochondria