The Role of the Adipokine Leptin in Immune Cell Function in Health and Disease

Frontiers in Immunology ◽

10.3389/fimmu.2020.622468 ◽

2021 ◽

Vol 11 ◽

Author(s):

Kaitlin Kiernan ◽

Nancie J. MacIver

Keyword(s):

Adipose Tissue ◽

Leptin Receptor ◽

Cell Function ◽

Immune Cell ◽

Immune Cell Function ◽

Tissue Mass ◽

Inflammatory Phenotype ◽

Health And Disease ◽

Pleiotropic Actions

Leptin is a critical mediator of the immune response to changes in overall nutrition. Leptin is produced by adipocytes in proportion to adipose tissue mass and is therefore increased in obesity. Despite having a well-described role in regulating systemic metabolism and appetite, leptin displays pleiotropic actions, and it is now clear that leptin has a key role in influencing immune cell function. Indeed, many immune cells have been shown to respond to leptin directly via the leptin receptor, resulting in a largely pro-inflammatory phenotype. Understanding the role of adipose-tissue derived mediators in inflammation is critical to determining the pathophysiology of multiple obesity-associated diseases, such as type 2 diabetes, autoimmune disease, and infection. This review, therefore, focuses on the latest data regarding the role of leptin in modulating inflammation.

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Bone Marrow Leptin Signaling Mediates Obesity-Associated Adipose Tissue Inflammation in Male Mice

Endocrinology ◽

10.1210/en.2013-1607 ◽

2014 ◽

Vol 155 (1) ◽

pp. 40-46 ◽

Cited By ~ 30

Author(s):

Lea H. Dib ◽

M. Teresa Ortega ◽

Sherry D. Fleming ◽

Stephen K. Chapes ◽

Tonatiuh Melgarejo

Keyword(s):

Bone Marrow ◽

Adipose Tissue ◽

Systemic Inflammation ◽

Leptin Receptor ◽

Cell Function ◽

Immune Cell ◽

Metabolic Complications ◽

Leptin Signaling ◽

Lower Body Weight ◽

Inflammatory Phenotype

Obesity is characterized by an increased recruitment of proinflammatory macrophages to the adipose tissue (AT), leading to systemic inflammation and metabolic disease. The pathogenesis of this AT inflammation, however, remains to be elucidated. The circulating adipokine leptin is increased in obesity and is involved in immune cell function and activation. In the present study, we investigated the role of leptin in the induction of obesity-associated inflammation. We generated radiation chimeric C57BL/6J mice reconstituted with either leptin receptor-deficient (db/db) or wild-type (WT) bone marrow and challenged them with a high-fat diet (HFD) for 16 weeks. Mice reconstituted with db/db bone marrow (WT/db), had significantly lower body weight and adiposity compared with mice with WT bone marrow (WT/WT). Gonadal AT in WT/db mice displayed a 2-fold lower expression of the inflammatory genes Tnfa, Il6, and Ccl2. In addition, gonadal fat of WT/db mice contained significantly fewer crown-like structures compared with WT/WT mice, and most of their AT macrophages expressed macrophage galactose-type C type lectin 1 (MGL1) and were C-C chemokine receptor type 2 (CCR2)-negative, indicative of an anti-inflammatory phenotype. Moreover, WT/db mice exhibited greater insulin sensitivity compared with WT/WT mice. These data show that disrupted leptin signaling in bone marrow-derived cells attenuates the proinflammatory conditions that mediate many of the metabolic complications that characterize obesity. Our findings establish a novel mechanism involved in the regulation of obesity-associated systemic inflammation and support the hypothesis that leptin is a proinflammatory cytokine.

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Molecular regulation of TLR signaling in health and disease: mechano-regulation of macrophages and TLR signaling

Innate Immunity ◽

10.1177/1753425919838322 ◽

2020 ◽

Vol 26 (1) ◽

pp. 15-25 ◽

Cited By ~ 4

Author(s):

Erika J Gruber ◽

Cynthia A Leifer

Keyword(s):

Cell Function ◽

Immune Cell ◽

Tissue Mechanics ◽

Physical Characteristics ◽

Immune Cell Function ◽

Tlr Signaling ◽

Cytokines And Chemokines ◽

Health And Disease ◽

Sense And Respond

Immune cells encounter tissues with vastly different biochemical and physical characteristics. Much of the research emphasis has focused on the role of cytokines and chemokines in regulating immune cell function, but the role of the physical microenvironment has received considerably less attention. The tissue mechanics, or stiffness, of healthy tissues varies dramatically from soft adipose tissue and brain to stiff cartilage and bone. Tissue mechanics also change due to fibrosis and with diseases such as atherosclerosis or cancer. The process by which cells sense and respond to their physical microenvironment is called mechanotransduction. Here we review mechanotransduction in immunologically important diseases and how physical characteristics of tissues regulate immune cell function, with a specific emphasis on mechanoregulation of macrophages and TLR signaling.

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HIF1α activation in dendritic cells under sterile conditions promotes an anti-inflammatory phenotype through accumulation of intracellular lipids

Scientific Reports ◽

10.1038/s41598-020-77793-6 ◽

2020 ◽

Vol 10 (1) ◽

Author(s):

Elizabeth G. Wood ◽

Claire E. Macdougall ◽

Hazel Blythe ◽

Marc Clément ◽

Romain A. Colas ◽

...

Keyword(s):

Adipose Tissue ◽

Cell Function ◽

Immune Cell ◽

Lipid Synthesis ◽

Mortality And Morbidity ◽

Intracellular Lipids ◽

Adipose Tissue Dysfunction ◽

Disease Mortality ◽

Key Factor ◽

Inflammatory Phenotype

AbstractObesity is among the leading causes of elevated cardiovascular disease mortality and morbidity. Adipose tissue dysfunction, insulin resistance and inflammation are recognized as important risk factors for the development of cardiovascular disorders in obesity. Hypoxia appears to be a key factor in adipose tissue dysfunction affecting not only adipocytes but also immune cell function. Here we examined the effect of hypoxia-induced transcription factor HIF1α activation on classical dendritic cell (cDCs) function during obesity. We found that deletion of Hif1α on cDCs results in enhanced adipose-tissue inflammation and atherosclerotic plaque formation in a mouse model of obesity. This effect is mediated by HIF1α-mediated increased lipid synthesis, accumulation of lipid droplets and alter synthesis of lipid mediators. Our findings demonstrate that HIF1α activation in cDCs is necessary to control vessel wall inflammation.

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MicroRNA-Regulated Immune Cell Function in Obese Adipose Tissue

Handbook of Nutrition, Diet, and Epigenetics ◽

10.1007/978-3-319-31143-2_26-1 ◽

2017 ◽

pp. 1-18

Author(s):

Beiyan Zhou ◽

Wei Ying ◽

Chuan Li ◽

Anthony T. Vella

Keyword(s):

Adipose Tissue ◽

Cell Function ◽

Immune Cell ◽

Immune Cell Function

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Where Is Dopamine and how do Immune Cells See it?: Dopamine-Mediated Immune Cell Function in Health and Disease

Journal of Neuroimmune Pharmacology ◽

10.1007/s11481-019-09851-4 ◽

2019 ◽

Vol 15 (1) ◽

pp. 114-164 ◽

Cited By ~ 12

Author(s):

S. M. Matt ◽

P. J. Gaskill

Keyword(s):

Immune Cells ◽

Cell Function ◽

Immune Cell ◽

Immune Cell Function ◽

Health And Disease

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Identification of a prostaglandin E2 receptor that regulates mosquito oenocytoid immune cell function in limiting bacteria and parasite infection

10.1101/2020.08.03.235432 ◽

2020 ◽

Author(s):

Hyeogsun Kwon ◽

David R. Hall ◽

Ryan C. Smith

Keyword(s):

Immune Responses ◽

Prostaglandin E2 ◽

Cell Function ◽

Immune Cell ◽

Protective Effects ◽

Immune Cell Function ◽

Humoral Immune ◽

High Concentrations ◽

Prostaglandin E2 Receptor

AbstractLipid-derived signaling molecules known as eicosanoids have integral roles in mediating immune and inflammatory processes across metazoans. This includes the function of prostaglandins and their cognate G protein-coupled receptors (GPCRs) to employ their immunological actions. In insects, prostaglandins have been implicated in the regulation of both cellular and humoral immune responses, yet studies have been limited by the absence of a described prostaglandin receptor. Here, we characterize a prostaglandin E2 receptor (AgPGE2R) in the mosquito Anopheles gambiae and examine its contributions to innate immunity. AgPGE2R expression is most abundant in circulating hemocytes where it is primarily localized to oenocytoid immune cell populations. Through the administration of prostaglandin E2 (PGE2) and AgPGE2R-silencing by RNAi, we demonstrate that PGE2 signaling regulates the expression of a subset of prophenoloxidases (PPOs) and antimicrobial peptides (AMPs). PGE2 priming via the AgPGE2R significantly limited bacterial replication and suppressed Plasmodium oocyst survival. Additional experiments establish that PGE2 priming increases phenoloxidase (PO) activity through the increased expression of PPO1 and PPO3, which significantly influence Plasmodium oocyst survival. We also provide evidence that PGE2 priming is concentration-dependent, where high concentrations of PGE2 promote oenocytoid lysis, negating the protective effects of PGE2 priming on anti-Plasmodium immunity. Taken together, our results characterize the AgPGE2R and the role of prostaglandin signaling on immune cell function, providing new insights into the role of PGE2 on anti-bacterial and anti-Plasmodium immune responses in the mosquito host.

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STAT3, a Master Regulator of Anti-Tumor Immune Response

Cancers ◽

10.3390/cancers11091280 ◽

2019 ◽

Vol 11 (9) ◽

pp. 1280 ◽

Cited By ~ 19

Author(s):

Rébé ◽

Ghiringhelli

Keyword(s):

Cancer Progression ◽

Immune Cells ◽

Cell Function ◽

Immune Cell ◽

Checkpoint Inhibitors ◽

Cancer Growth ◽

Signal Transducer ◽

Immune Cell Function ◽

Transcription 3

Immune cells in the tumor microenvironment regulate cancer growth. Thus cancer progression is dependent on the activation or repression of transcription programs involved in the proliferation/activation of lymphoid and myeloid cells. One of the main transcription factors involved in many of these pathways is the signal transducer and activator of transcription 3 (STAT3). In this review we will focus on the role of STAT3 and its regulation, e.g. by phosphorylation or acetylation in immune cells and how it might impact immune cell function and tumor progression. Moreover, we will review the ability of STAT3 to regulate checkpoint inhibitors.

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