An Approach to Reducing Inflammatory Immune Cell Activity in Fat Tissue
The growing costs of obesity have prompted considerable research and development efforts focused on pharmacological approaches to weight loss. Another possible avenue is to develop drugs to reduce some of the negative impacts of aged and excess fat tissue, such as the chronic inflammatory signaling produced by visceral fat. While it is reasonable to argue that weight loss is the preferential approach for people who are overweight, comprehensive rejuvenation is not yet a reality and older people, even thin older people, undergo poorly understood and incompletely mapped changes in cell biochemistry and immune function that make fat tissue more inflammatory.
Inflammation in fat tissue is a function of the immune system, provoked by the metabolic activity of fat cells. Chronic, unresolved inflammation is harmful to tissue function throughout the body, contributing to the onset and progress of age-related disease. In today's open access paper, researchers discuss a potential regulator of this inflammation. They show that inhibiting the interaction between innate immune cell receptor BLT1 and its binding ligand LTB4 reduces both obesity-related and age-related inflammatory immune cell behavior in fat tissue.
Role for BLT1 in regulating inflammation within adipose tissue immune cells of aged mice
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 cells 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.
In conclusion, 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.