TL1A regulates adipose-resident innate lymphoid immune responses and enables diet-induced obesity in mice

Tougaard, Peter; Martinsen, Louise; Lützhøft, Ditte Olsen; Jensen, Henrik Elvang; Flethøj, Mette; Vandenabeele, Peter; Pedersen, Anders Elm; Skov, Søren; Hansen, Axel Kornerup; Hansen, Camilla Hartmann Friis

doi:10.1038/s41366-020-0539-1

Cited by 8 publications

(8 citation statements)

References 45 publications

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“…TL1A, another well-characterized TNFSF, has mostly been studied for its involvement in inflammatory and autoimmune diseases but has only recently been implicated in obesity ( 41 ). We found increased TL1A expression in adipose tissue in a TRAIL-dependent manner, consistent with TRAIL-TL1A coupling, as was previously shown in skin lesions of patients with diabetes ( 42 ).…”

Section: Discussionmentioning

confidence: 99%

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

et al. 2020

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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.

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Section: Discussionmentioning

confidence: 99%

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

et al. 2020

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“…On the other hand, previously, it had been shown that an HFD which induced obesity in mice, also increased γδ cells in inguinal fat [36] and that the γδ T cells increase in fatty tissue in obese mice was less pronounced in leptin-deficient mice, suggesting a role for leptin in the control of AT γδ T cells [37]. An additional factor controlling the homeostasis of γδ T cells in obesity may be TNF-like cytokine 1A (TL1A), a TNFα-related molecule [38]. Thus, TL1A deficient mice were both less obese and had fewer γδ T cells in epididymal white fat, concomitant with a reduction of mitochondria regulatory genes.…”

Section: Physiology Of γδ T Cells In Atmentioning

confidence: 99%

“…Thus, TL1A deficient mice were both less obese and had fewer γδ T cells in epididymal white fat, concomitant with a reduction of mitochondria regulatory genes. Interestingly, in humans, a non-coding polymorphism close to the TL1A locus was associated with body mass, suggesting that studies of AT γδ cells in these individuals would be of interest [38]. Others have reported that HFD may specifically induce an increase of CD44 + CD62lo γδ T cells in epididymal fat of mice.…”

Section: Physiology Of γδ T Cells In Atmentioning

confidence: 99%

Obesity and cancer: the gammadelta T cell link

Bank

2022

Explor Immunol

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Obesity has become a worldwide scourge, affecting more than 10% of adults worldwide. While widely recognized to be associated with increased incidence of medical conditions such as diabetes mellitus and atherosclerosis, obesity also accounts for 9% of the cancer burden in some populations. This is due in part to perturbation of protective immune mechanisms involving natural killer cells, macrophages, and neutrophils. Recent studies indicate that γδ T cells play a prominent protective role against cancer, but in some circumstances are detrimental and pro tumorogenic. In this review, the current scientific literature was explored to determine whether and how obesity affects the anti- and pro-tumoral functions of γδ T cells. Considerable perturbations of γδ T cells by obesity were revealed, suggesting that the “obesity-γδ T cell axis” may profoundly impact the increased incidence of cancer in obese individuals and is worthy of further study.

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“…Although TL1A expression has been explored in a variety of different contexts ( 221 ), the role of TL1A in adipose has yet to be fully explored. In one study, TL1A-deficient HFD mice showed decreased adiposity, glucose tolerance, but also reduced expression of UCP1 ( 223 ). It was also found that TL1A deficiency also reduced the abundance of ILC1s.…”

Section: New Perspectives Of Ilc2s In T2dmmentioning

confidence: 99%

Type 2 Innate Lymphoid Cells: Protectors in Type 2 Diabetes

Painter

Akbari

2021

Front. Immunol.

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Type 2 innate lymphoid cells (ILC2) are the innate counterparts of Th2 cells and are critically involved in the maintenance of homeostasis in a variety of tissues. Instead of expressing specific antigen receptors, ILC2s respond to external stimuli such as alarmins released from damage. These cells help control the delicate balance of inflammation in adipose tissue, which is a determinant of metabolic outcome. ILC2s play a key role in the pathogenesis of type 2 diabetes mellitus (T2DM) through their protective effects on tissue homeostasis. A variety of crosstalk takes place between resident adipose cells and ILC2s, with each interaction playing a key role in controlling this balance. ILC2 effector function is associated with increased browning of adipose tissue and an anti-inflammatory immune profile. Trafficking and maintenance of ILC2 populations are critical for tissue homeostasis. The metabolic environment and energy source significantly affect the number and function of ILC2s in addition to affecting their interactions with resident cell types. How ILC2s react to changes in the metabolic environment is a clear determinant of the severity of disease. Treating sources of metabolic instability via critical immune cells provides a clear avenue for modulation of systemic homeostasis and new treatments of T2DM.

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TL1A regulates adipose-resident innate lymphoid immune responses and enables diet-induced obesity in mice

Cited by 8 publications

References 45 publications

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

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

Obesity and cancer: the gammadelta T cell link

Type 2 Innate Lymphoid Cells: Protectors in Type 2 Diabetes

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