A TRAIL-TL1A Paracrine Network Involving Adipocytes, Macrophages, and Lymphocytes Induces Adipose Tissue Dysfunction Downstream of E2F1 in Human Obesity

Abstract

Elevated expression of E2F1 in adipocyte fraction of human visceral adipose tissue (hVAT) associates with a poor cardiometabolic profile. We hypothesized that beyond directly activating autophagy and MAP3K5 (ASK)–MAP kinase signaling, E2F1 governs a distinct transcriptome that contributes to adipose tissue and metabolic dysfunction in obesity. We performed RNA sequencing of hVAT samples from age-, sex-, and BMI-matched patients, all obese, whose visceral E2F1 protein expression was either high (E2F1 high ) or low (E2F1 low ). Tumor necrosis factor superfamily (TNFSF) members, including TRAIL ( TNFSF10 ), TL1A ( TNFSF15 ), and their receptors, were enriched in E2F1 high . While TRAIL was equally expressed in adipocytes and stromal vascular fraction (SVF), TL1A was mainly expressed in SVF, and TRAIL-induced TL1A was attributed to CD4 + and CD8 + subclasses of hVAT T cells. In human adipocytes, TL1A enhanced basal and impaired insulin-inhibitable lipolysis and altered adipokine secretion, and in human macrophages it induced foam cell biogenesis and M1 polarization. Two independent human cohorts confirmed associations between TL1A and TRAIL expression in hVAT and higher leptin and IL6 serum concentrations, diabetes status, and hVAT-macrophage lipid content. Jointly, we propose an intra-adipose tissue E2F1-associated TNFSF paracrine loop engaging lymphocytes, macrophages, and adipocytes, ultimately contributing to adipose tissue dysfunction in obesity.

High-dimensional profiling demonstrates complexity, tissue imprinting, and lineage-specific precursors within the mononuclear phagocyte compartment of the human intestine

“…They did however resemble adipose tissue macrophages in several respects(Frey and Vogel, 2011; Li et al, 2020), including activity of the TRAIL pathway ( Fig. 4E ) (Maixner et al, 2020).…”

The relationship between TNF-like protein 1A and coronary artery aneurysms in children with Kawasaki disease

“…It has been reported that TL1A can regulate metabolism [8,16] in physiological status and play an important role in the modulation of vascular homeostasis and autoimmune diseases [5,7] . The pathogenesis of KD is well known as in ammation and imbalance of immunology resulting in vascular lesion.…”

“…TL1A is primarily produced by endothelial cells under stimulation of TNF-α and IL-1, and is also expressed in the lymphocytes, macrophages, dendritic cells, chondrocytes and synovial cells [6] . TL1A could stimulate T cell activation, proliferation, and production of large amounts of essential cytokines via death receptor 3 (DR3), which is expressed mainly on lymphocytes [5] .TL1A plays an important role in apoptosis, modulation of immune responses, vascular homeostasis, glucose and lipid metabolism [5,7,8] . McLaren et al [9] have demonstrated that TL1A promotes the formation of foam cell in vitro by regulating the levels of low-density lipoprotein and cholesterol that are involved in atherosclerosis.…”

Type 2 Innate Lymphoid Cells: Protectors in Type 2 Diabetes

“…DR3 stimulation also provides a more significant activation of human ILC2s in comparison to GITR ( 28 ). Recently, it was found that human cells from stromal cell vascular fractions in adipose tissue induced TL1A expression in response to TNF-related apoptosis-inducing ligand (TRAIL) significantly more in comparison to other cell types ( 145 ). TRAIL is commonly associated with a variety of obesity-related diseases and plays a role in human adipocyte inflammation ( 146 ).…”