Obesity-induced dysregulation of skin-resident PPARγ+ Treg cells promotes IL-17A-mediated psoriatic inflammation

Sivasami, Pulavendran; Elkins, Cody M; Goss, Kyndal; Peng, A; Hamersky, Michael; Bae, Ji‐Hoon; Xu, Meifeng; Pollack, Brian P.; Horwitz, Edwin M.; Scharer, Christopher D.; Seldin, Lindsey; Li, Chaoran

doi:10.1016/j.immuni.2023.06.021

Cited by 36 publications

(4 citation statements)

References 78 publications

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“…To validate this hypothesis, we utilized sulfosuccinimidyl oleate (SSO), a CD36 inhibitor, to evaluate its impact on nanoparticle uptake by HCC cells. 23 Indeed, SSO pretreatment reduced cellular uptake of hybrid adipocyte-derived exosome (Figure 2E, F). In light of our finding, we summarized the brief caveolae-mediated endocytosis mechanism (Figure 2G).…”

Section: Resultsmentioning

confidence: 91%

Hybrid Adipocyte-Derived Exosome Nano Platform for Potent Chemo-Phototherapy in Targeted Hepatocellular Carcinoma

Liu,

Zhang,

Zheng

et al. 2023

Preprint

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The high prevalence and severity of hepatocellular carcinoma (HCC) present a significant menace to human health. Despite the significant advancements in nanotechnology-driven antineoplastic agents, there remains a conspicuous gap in the development of targeted chemotherapeutic agents specifically designed for HCC. Consequently, there is an urgent need to explore potent drug delivery systems for effective HCC treatment. Here we have exploited the interplay between HCC and adipocyte to engineer a hybrid adipocyte-derived exosome platform, serving as a versatile vehicle to specifically target HCC and exsert potent antitumor effect. A lipid-like prodrug of docetaxel (DSTG) with a reactive oxygen species (ROS)-cleavable linker, and a lipid-conjugated photosensitizer (PPLA), spontaneously co-assemble into nanoparticles, functioning as the lipid cores of the hybrid exosomes (HEMPs and NEMPs). These nanoparticles are further encapsuled within adipocyte-derived exosome membranes, enhancing their affinity towards HCC cancer cells. As such, cancer cell uptakes of hybrid exosomes are increased up to 5.73-fold compared to lipid core nanoparticles. Ourin vitroandin vivoexperiments have demonstrated that HEMPs not only enhance the bioactivity of the prodrug and extend its circulation in the bloodstream but also effectively inhibit tumor growth by selectively targeting hepatocellular carcinoma tumor cells. Self-facilitated synergistic drug release subsequently promoting antitumor efficacy, inducing significant inhibition of tumor growth with minimal side effects. Our findings herald a promising direction for the development of targeted HCC therapeutics.Graphical abstractAn adipocyte-derived exosome nanoplatform has been developed for the combined therapy of both chemotherapy and photodynamic therapy. The hybrid adipocyte-derived exosome nanoplatform integrates the advantage of targeted co-delivery and combination therapy, which can stimulate the release of drugs under the tumor microenvironment, effectively enhanced targeted co-delivery in hepatocellular carcinoma cells, prolonged blood circulation time and improve the therapeutic effect of hepatocellular carcinoma tumors model.

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Section: Resultsmentioning

confidence: 91%

Hybrid Adipocyte-Derived Exosome Nano Platform for Potent Chemo-Phototherapy in Targeted Hepatocellular Carcinoma

Liu,

Zhang,

Zheng

et al. 2023

Preprint

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“…These include scavenger proteins such as CD36 and enzymes involved in triglyceride production, such as DGAT1 and DGAT2. Skin and VAT-isolated PPARγ + T REG cells readily express CD36, providing them with the ability to capture and secure LCFAs ( 175 , 180 ). DGAT are a family of enzymes involved in triglyceride production and lipid droplet (LD) formation that are preferentially expressed in activated T REG cells ( 181 ).…”

Section: The Unique Properties Of Tr-t Reg Cellsmentioning

confidence: 99%

Deciphering the developmental trajectory of tissue-resident Foxp3+ regulatory T cells

Alvarez,

Liu,

Bay

et al. 2024

Front. Immunol.

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Foxp3+ TREG cells have been at the focus of intense investigation for their recognized roles in preventing autoimmunity, facilitating tissue recuperation following injury, and orchestrating a tolerance to innocuous non-self-antigens. To perform these critical tasks, TREG cells undergo deep epigenetic, transcriptional, and post-transcriptional changes that allow them to adapt to conditions found in tissues both at steady-state and during inflammation. The path leading TREG cells to express these tissue-specialized phenotypes begins during thymic development, and is further driven by epigenetic and transcriptional modifications following TCR engagement and polarizing signals in the periphery. However, this process is highly regulated and requires TREG cells to adopt strategies to avoid losing their regulatory program altogether. Here, we review the origins of tissue-resident TREG cells, from their thymic and peripheral development to the transcriptional regulators involved in their tissue residency program. In addition, we discuss the distinct signalling pathways that engage the inflammatory adaptation of tissue-resident TREG cells, and how they relate to their ability to recognize tissue and pathogen-derived danger signals.

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“…Interestingly, obesity, especially long-chain FFAs, causes Treg loss in the skin and simultaneously increases IL-17A+ γδ T cells by reducing PPARγ+ skin Treg cells and a corresponding loss of control over IL-17A+ γδ T cell-mediated inflammation. Therefore, obesity plays a key role in the development of psoriasis [ 231 ].…”

Section: Immune Cells In Psoriasismentioning

confidence: 99%

The Immunology of Psoriasis—Current Concepts in Pathogenesis

Sieminska,

Pieniawska,

Grzywa

2024

Clinic Rev Allerg Immunol

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Psoriasis is one of the most common inflammatory skin diseases with a chronic, relapsing-remitting course. The last decades of intense research uncovered a pathological network of interactions between immune cells and other types of cells in the pathogenesis of psoriasis. Emerging evidence indicates that dendritic cells, TH17 cells, and keratinocytes constitute a pathogenic triad in psoriasis. Dendritic cells produce TNF-α and IL-23 to promote T cell differentiation toward TH17 cells that produce key psoriatic cytokines IL-17, IFN-γ, and IL-22. Their activity results in skin inflammation and activation and hyperproliferation of keratinocytes. In addition, other cells and signaling pathways are implicated in the pathogenesis of psoriasis, including TH9 cells, TH22 cells, CD8+ cytotoxic cells, neutrophils, γδ T cells, and cytokines and chemokines secreted by them. New insights from high-throughput analysis of lesional skin identified novel signaling pathways and cell populations involved in the pathogenesis. These studies not only expanded our knowledge about the mechanisms of immune response and the pathogenesis of psoriasis but also resulted in a revolution in the clinical management of patients with psoriasis. Thus, understanding the mechanisms of immune response in psoriatic inflammation is crucial for further studies, the development of novel therapeutic strategies, and the clinical management of psoriasis patients. The aim of the review was to comprehensively present the dysregulation of immune response in psoriasis with an emphasis on recent findings. Here, we described the role of immune cells, including T cells, B cells, dendritic cells, neutrophils, monocytes, mast cells, and innate lymphoid cells (ILCs), as well as non-immune cells, including keratinocytes, fibroblasts, endothelial cells, and platelets in the initiation, development, and progression of psoriasis.

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Obesity-induced dysregulation of skin-resident PPARγ+ Treg cells promotes IL-17A-mediated psoriatic inflammation

Cited by 36 publications

References 78 publications

Hybrid Adipocyte-Derived Exosome Nano Platform for Potent Chemo-Phototherapy in Targeted Hepatocellular Carcinoma

Hybrid Adipocyte-Derived Exosome Nano Platform for Potent Chemo-Phototherapy in Targeted Hepatocellular Carcinoma

Deciphering the developmental trajectory of tissue-resident Foxp3+ regulatory T cells

The Immunology of Psoriasis—Current Concepts in Pathogenesis

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