Senescent immune cells accumulation promotes brown adipose tissue dysfunction during aging

Brown adipose tissue (BAT) plays a crucial role in non-shivering thermogenesis, contributing significantly to metabolic health. However, BAT function declines with age, exhibiting increased adiposity, inflammatory immune cell infiltration, and reduced thermogenesis, ultimately leading to obesity and age-related metabolic disorders. Immunosenescence, the aging of the immune system, is increasingly recognized as a key contributor to the aging of various organs, including adipose tissue. The specific role of senescent immune cells in BAT aging, however, remains largely unexplored. The sympathetic nervous system (SNS) is vital for BAT function, directly innervating BAT and driving adipocyte lipolysis and adaptive thermogenesis via noradrenaline release. Recent research highlights the interplay between the nervous and immune systems in regulating adipose tissue function, but the cooperative mechanisms between sympathetic neurons and immune cells in BAT, particularly during aging and its associated impaired sympathetic innervation, require further investigation. S100A8, a calcium-binding protein, is a crucial alarmin modulating the inflammatory response. Its extracellular form interacts with pattern recognition receptors, promoting cell activation and recruitment. Studies using single-cell RNA sequencing (scRNA-seq) have identified S100A8 as a significantly increased protein in aged rat BAT, suggesting a potential role in accelerating BAT aging. This study aimed to investigate the role of senescent immune cells in BAT aging, focusing on the involvement of S100A8 and its potential as a therapeutic target.

Existing literature demonstrates a decline in BAT-mediated thermogenesis with age, but the underlying mechanisms remain unclear. Studies have linked immunosenescence to the aging of solid organs, including white adipose tissue, but the role of senescent immune cells in BAT aging was previously unknown. The importance of the sympathetic nervous system (SNS) in driving BAT function is well-established, with research highlighting the interactions between the nervous and immune systems in regulating adipose tissue function. The alarmin S100A8 has emerged as a key player in inflammation and leukocyte recruitment. Single-cell RNA sequencing data indicated elevated S100A8 in the BAT of aged rats, prompting investigation into its potential role in BAT aging.

The study employed a multi-faceted approach. Initially, scRNA-seq data of BAT from young and aged rats was reanalyzed to identify immune cell populations contributing to BAT aging. This analysis focused on S100A8 expression in various immune cells. Further experiments utilized mice to investigate the origin of BAT-infiltrating S100A8+ immune cells. Bone marrow-derived S100A8+ and S100A8- immune cells were isolated and transplanted into young mice to assess their impact on BAT function. Bone marrow chimeric mice were also generated to confirm the bone marrow origin of the infiltrating cells. Metabolic phenotypes were assessed through indirect calorimetry, measuring oxygen consumption, energy expenditure, and core body temperature. RNA sequencing was performed to identify S100A8 downstream targets and to study RBM3 function. RBM3 expression was manipulated in vivo and in vitro, and RNA immunoprecipitation sequencing (RIP-seq) was used to identify direct target genes of RBM3. The study also included in vitro experiments using differentiated brown adipocytes and PC12 cells to assess the effects of S100A8 and RBM3. Finally, human S100A8+ immune cells were transplanted into immunodeficient mice to evaluate their effects on BAT function. The effect of paquinimod, an S100A8/A9 inhibitor, on BAT aging and metabolic dysfunction was also investigated in aged mice fed normal chow and high-fat diets.

The study found that pro-inflammatory and senescent S100A8+ immune cells (mainly T cells and neutrophils) accumulate in the BAT of aged rats and mice. These cells originate from the bone marrow and preferentially infiltrate BAT. Transplantation of S100A8+ immune cells into young mice impaired BAT thermogenic function, reducing oxygen consumption, energy expenditure, and core body temperature. S100A8+ immune cells, along with sympathetic nerves and adipocytes, form neuroimmune interfaces that inhibit sympathetic innervation. Mechanistically, S100A8 decreases RBM3 expression in brown adipocytes, leading to dysregulation of axon guidance-related genes and impaired sympathetic innervation. RBM3 knockdown in mice mimicked the effects of S100A8+ immune cell infiltration, while RBM3 overexpression rescued the BAT dysfunction. Human S100A8+ immune cells also induced BAT aging and thermogenic decline in mice. Treatment with paquinimod, an S100A8 inhibitor, reversed these effects, improving BAT function and ameliorating age-related metabolic dysfunction in both normal chow and high-fat diet-fed mice.

This study provides compelling evidence for the role of bone marrow-derived senescent S100A8+ immune cells in driving BAT aging. The formation of a neuroimmune adipose interface, where these cells interact with sympathetic nerves and adipocytes, is a novel finding that explains the mechanism of impaired sympathetic innervation. The identification of RBM3 as a key downstream target of S100A8 provides a crucial mechanistic link between immune cell senescence, reduced sympathetic innervation, and BAT dysfunction. The success of paquinimod in reversing these effects highlights its potential as a therapeutic agent for age-related metabolic disorders. The study also demonstrates the translational relevance of the findings by showing that human S100A8+ immune cells can induce similar BAT dysfunction in mice. This research significantly advances our understanding of BAT aging and opens new avenues for therapeutic interventions.

This study reveals a novel mechanism for age-related BAT dysfunction, highlighting the crucial role of bone marrow-derived S100A8+ senescent immune cells in inhibiting sympathetic innervation via the downregulation of RBM3 in brown adipocytes. The successful use of paquinimod underscores its therapeutic potential. Future research could explore the specific signaling pathways involved in the S100A8-RBM3 axis, identify additional target genes of RBM3, and investigate the potential of paquinimod in human clinical trials for age-related metabolic disorders.

The study primarily used male mice, limiting the generalizability of the findings to females. The relatively small sample size in some experiments might limit the statistical power. Further investigation is needed to fully elucidate the complex interactions within the neuroimmune adipose interface and to assess the long-term effects of paquinimod treatment.