Loss of Mir146b with aging contributes to inflammation and mitochondrial dysfunction in thioglycollate-elicited...

Area of Science:

• Immunology
• Molecular Biology
• Gerontology

Background:

• Macrophages play a crucial role in immune responses but undergo age-related changes, leading to immune dysfunction.
• These age-associated alterations, termed inflammaging, can shift macrophages from protective roles to promoting disease.
• The precise molecular mechanisms driving macrophage inflammaging remain largely unknown.

Purpose of the Study:

• To investigate the molecular mechanisms underlying age-related changes in macrophages.
• To identify key regulatory factors, such as microRNAs, involved in macrophage inflammaging.
• To understand the functional consequences of altered microRNA expression in aging macrophages.

Main Methods:

• Unbiased RNA sequencing (RNA-seq) was employed to identify microRNAs with age-dependent expression patterns in murine macrophages.
• Quantitative analysis of microRNA expression in macrophages from aged and young mice.
• Functional assays were performed on macrophages with experimentally altered Mir146b expression, including cytokine profiling and mitochondrial metabolic activity assessment.
• Single-cell RNA sequencing (scRNA-seq) was utilized to analyze inflammatory and signaling pathway alterations in Mir146b-deficient macrophages.

Main Results:

• A significant, progressive decline in microRNA-146b (Mir146b) expression was observed with increasing age in murine macrophages.
• Mir146b deficiency in macrophages resulted in altered expression of key cytokines, indicative of an inflammatory shift.
• Macrophages lacking Mir146b exhibited reduced mitochondrial metabolic activity, a hallmark of cellular aging.
• Single-cell RNA-seq revealed dysregulated inflammation and interferon gamma signaling pathways in Mir146b-deficient macrophages.

Conclusions:

• MicroRNA-146b (Mir146b) emerges as a critical regulator of macrophage aging.
• The age-dependent decrease in Mir146b contributes to inflammaging and immune dysfunction.
• Targeting Mir146b may offer a novel therapeutic strategy for age-related immune disorders.