Shih Wei-Ching, Jang In Hwa, Kruglov Victor, Dickey Deborah, Cholensky Stephanie, Bernlohr David A, Camell Christina D
Department of Pharmacology, Molecular Pharmacology and Therapeutics Graduate Program, University of Minnesota, Minneapolis, MN, USA.
Department of Biochemistry, Molecular Biology and Biophysics, Institute on the Biology of Aging and Metabolism, University of Minnesota, Minneapolis, MN, USA.
Immun Ageing. 2024 Aug 26;21(1):57. doi: 10.1186/s12979-024-00461-0.
Aging is a complex biological process characterized by obesity and immunosenescence throughout the organism. Immunosenescence involves a decline in immune function and the increase in chronic-low grade inflammation, called inflammaging. Adipose tissue expansion, particularly that of visceral adipose tissue (VAT), is associated with an increase in pro-inflammatory macrophages that play an important role in modulating immune responses and producing inflammatory cytokines. The leukotriene B4 receptor 1 (BLT1) is a regulator of obesity-induced inflammation. Its ligand, LTB4, acts as a chemoattractant for immune cells and induces inflammation. Studies have shown that BLT1 is crucial for cytokine production during lipopolysaccharide (LPS) endotoxemia challenge in younger organisms. However, the expression patterns and function of BLT1 in older organisms remains unknown.
In this study, we investigated BLT1 expression in immune cell subsets within the VAT of aged male and female mice. Moreover, we examined how antagonizing BLT1 signaling could alter the inflammatory response to LPS in aged mice. Our results demonstrate that aged mice exhibit increased adiposity and inflammation, characterized by elevated frequencies of B and T cells, along with pro-inflammatory macrophages in VAT. BLT1 expression is the highest in VAT macrophages. LPS and LTB4 treatment result in increased BLT1 in young and aged bone marrow-derived macrophages (BMDMs). However, LTB4 treatment resulted in amplified Il6 from aged, but not young BMDMs. Treatment of aged mice with the BLT1 antagonist, U75302, followed by LPS-induced endotoxemia resulted in an increase in anti-inflammatory macrophages, reduced phosphorylated NFκB and reduced Il6.
This study provides valuable insights into the age- and sex- specific changes in BLT1 expression on immune cell subsets within VAT. This study offers support for the potential of BLT1 in modulating inflammation in aging.
衰老为一个复杂的生物学过程，其特征为机体整体肥胖及免疫衰老。免疫衰老涉及免疫功能下降以及慢性低度炎症增加，即炎性衰老。脂肪组织扩张，尤其是内脏脂肪组织（VAT）的扩张，与促炎巨噬细胞增多相关，这些巨噬细胞在调节免疫反应和产生炎性细胞因子方面发挥重要作用。白三烯B4受体1（BLT1）是肥胖诱导炎症的调节因子。其配体白三烯B4（LTB4）作为免疫细胞的趋化因子并诱导炎症。研究表明，在较年轻机体中，BLT1在脂多糖（LPS）内毒素血症攻击期间对细胞因子产生至关重要。然而，BLT1在较老机体中的表达模式及功能仍不清楚。
在本研究中，我们调查了BLT1在老年雄性和雌性小鼠VAT内免疫细胞亚群中的表达。此外，我们研究了拮抗BLT1信号传导如何改变老年小鼠对LPS的炎症反应。我们的结果表明，老年小鼠表现出肥胖和炎症增加，其特征为VAT中B细胞和T细胞以及促炎巨噬细胞的频率升高。BLT1在VAT巨噬细胞中的表达最高。LPS和LTB4处理导致年轻和老年骨髓来源巨噬细胞（BMDM）中BLT1增加。然而，LTB4处理导致老年BMDM而非年轻BMDM中白细胞介素6（Il6）扩增。用BLT1拮抗剂U75302处理老年小鼠，随后进行LPS诱导的内毒素血症，导致抗炎巨噬细胞增加、磷酸化核因子κB减少以及Il6减少。
本研究为VAT内免疫细胞亚群中BLT1表达的年龄和性别特异性变化提供了有价值的见解。本研究为BLT1在调节衰老炎症中的潜力提供了支持。
