Macrophage alterations within the mesenteric lymphatic tissue are associated with impairment of lymphatic pump in metabolic syndrome

Zawieja, Scott D.; Wang, Wei; Chakraborty, Sanjukta; Zawieja, David C.; Muthuchamy, Mariappan

doi:10.1111/micc.12307

Cited by 36 publications

(56 citation statements)

References 83 publications

(184 reference statements)

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“…At this condition, one would expect that lymph filling would be decreased, which consequently decreases the phasic contractile frequency and the lymphatic pump flow in the MetSyn condition. In addition, we have shown that resident and innate immune cells, NO production, and expression of cytokines and chemokines modulate lymphatic function during MetSyn and lymphatic inflammation (23, 52). Our current studies on the complete profile of contractile and regulatory proteins of lymphatic vessels from MetSyn and the isolated vessels cultured in HG and insulin conditions and with inflammatory cytokines/chemokines would provide additional insights into the remodeling and function of lymphatics under these conditions.…”

Section: Discussionmentioning

confidence: 99%

“…Studies have also shown that insulin resistance is associated with increased macrophage infiltration that is mediated by MCP1 (89). We have shown that MCP1 is induced in LPS‐treated LMCs and is a significant chemoattractant for M1 macrophage polarization in lymphatic vessels and adjacent areas in MetSyn animals (52). Therefore, MCP1 induction is a crucial precursor for more widespread inflammation during insulin resistance, through active recruitment of inflammatory macrophages.…”

Section: Discussionmentioning

confidence: 99%

“…The cDNA was mixed with SYBR Green PCR master mix (Thermo Fisher Scientific). Primers specific to IL‐1β, IL‐6, iNOS, TNF‐α, monocyte chemoattractant protein (MCP)‐1, macrophage inflammatory protein (MIP)‐2, and IL‐8 were designed as indicated in our previous studies (49, 52). RPL19 was used as an internal loading control.…”

Section: Methodsmentioning

confidence: 99%

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Hyperglycemia‐ and hyperinsulinemia‐induced insulin resistance causes alterations in cellular bioenergetics and activation of inflammatory signaling in lymphatic muscle

Lee

Fluckey²,

Chakraborty

et al. 2017

FASEB j.

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Insulin resistance is a well-known risk factor for obesity, metabolic syndrome (MetSyn) and associated cardiovascular diseases, but its mechanisms are undefined in the lymphatics. Mesenteric lymphatic vessels from MetSyn or LPS-injected rats exhibited impaired intrinsic contractile activity and associated inflammatory changes. Hence, we hypothesized that insulin resistance in lymphatic muscle cells (LMCs) affects cell bioenergetics and signaling pathways that consequently alter contractility. LMCs were treated with different concentrations of insulin or glucose or both at various time points to determine insulin resistance. Onset of insulin resistance significantly impaired glucose uptake, mitochondrial function, oxygen consumption rates, glycolysis, lactic acid, and ATP production in LMCs. Hyperglycemia and hyperinsulinemia also impaired the PI3K/Akt while enhancing the ERK/p38MAPK/JNK pathways in LMCs. Increased NF-κB nuclear translocation and macrophage chemoattractant protein-1 and VCAM-1 levels in insulin-resistant LMCs indicated activation of inflammatory mechanisms. In addition, increased phosphorylation of myosin light chain-20, a key regulator of lymphatic muscle contraction, was observed in insulin-resistant LMCs. Therefore, our data elucidate the mechanisms of insulin resistance in LMCs and provide the first evidence that hyperglycemia and hyperinsulinemia promote insulin resistance and impair lymphatic contractile status by reducing glucose uptake, altering cellular metabolic pathways, and activating inflammatory signaling cascades.-Lee, Y., Fluckey, J. D., Chakraborty, S., Muthuchamy, M. Hyperglycemia- and hyperinsulinemia-induced insulin resistance causes alterations in cellular bioenergetics and activation of inflammatory signaling in lymphatic muscle.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Hyperglycemia‐ and hyperinsulinemia‐induced insulin resistance causes alterations in cellular bioenergetics and activation of inflammatory signaling in lymphatic muscle

Lee

Fluckey²,

Chakraborty

et al. 2017

FASEB j.

Self Cite

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“…In rats treated with LPS, decreased neutrophil association with mesenteric collecting lymphatics, and increased accumulation of CD163 + CD206 + macrophages (M2 phenotype) accompanied impaired lymphatic contractions, however the cause-effect relationships are not clear (178). In a rat model of metabolic syndrome, macrophages with the M1 phenotype (CD163 + MHCII + ) accumulated near mesenteric lymphatic vessels, and were associated with impaired pumping that could be partially restored with blockade of NOS or K ATP channels (1203). Still, the direct impact of these cells on lymphatic contractile activity remains to be determined.…”

Section: Lymphangions and The Lymphatic Pump Mechanismmentioning

confidence: 99%

Lymphatic Vessel Network Structure and Physiology

Breslin

Yang

Scallan

et al. 2018

Comprehensive Physiology

263

258

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The lymphatic system is comprised of a network of vessels interrelated with lymphoid tissue, which has the holistic function to maintain the local physiologic environment for every cell in all tissues of the body. The lymphatic system maintains extracellular fluid homeostasis favorable for optimal tissue function, removing substances that arise due to metabolism or cell death, and optimizing immunity against bacteria, viruses, parasites, and other antigens. This article provides a comprehensive review of important findings over the past century along with recent advances in the understanding of the anatomy and physiology of lymphatic vessels, including tissue/organ specificity, development, mechanisms of lymph formation and transport, lymphangiogenesis, and the roles of lymphatics in disease.

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“…lipopolysaccharide), and hence initiates the inflammatory immune cascade of macrophage and dendritic cell activation: a cycle of inflammation that likely further alters lymphatic function. 74,75 Lymph leaked in the mesentery is also fatty acid-rich and highly adipogenic, causing expansion of the adipose tissue surrounding the collecting mesenteric vessels. 74,76 In chronic inflammatory bowel diseases from ulcerative colitis to Crohn's disease, lacteals dilate, submucosal edema occurs, and initial lymphatic capillaries proliferate.…”

Section: Lymphangiogenesis In Intestinal Inflammationmentioning

confidence: 99%

Lymphangiogenesis: fuel, smoke, or extinguisher of inflammation’s fire?

Abouelkheir

Upchurch

Rutkowski

2017

Exp Biol Med (Maywood)

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Lymphangiogenesis is a recognized hallmark of inflammatory processes in tissues and organs as diverse as the skin, heart, bowel, and airways. In clinical and animal models wherein the signaling processes of lymphangiogenesis are manipulated, most studies demonstrate that an expanded lymphatic vasculature is necessary for the resolution of inflammation. The fundamental roles that lymphatics play in fluid clearance and immune cell trafficking from the periphery make these results seemingly obvious as a mechanism of alleviating locally inflamed environments: the lymphatics are simply providing a drain. Depending on the tissue site, lymphangiogenic mechanism, or induction timeframe, however, evidence shows that inflammation-associated lymphangiogenesis (IAL) may worsen the pathology. Recent studies have identified lymphatic endothelial cells themselves to be local regulators of immune cell activity and its consequential phenotypes – a more active role in inflammation regulation than previously thought. Indeed, results focusing on the immunocentric roles of peripheral lymphatic function have revealed that the basic drainage task of lymphatic vessels is a complex balance of locally processed and transported antigens as well as interstitial cytokine and immune cell signaling: an interplay that likely defines the function of IAL. This review will summarize the latest findings on how IAL impacts a series of disease states in various tissues in both preclinical models and clinical studies. This discussion will serve to highlight some emerging areas of lymphatic research in an attempt to answer the question relevant to an array of scientists and clinicians of whether IAL helps to fuel or extinguish inflammation. Impact statement Inflammatory progression is present in acute and chronic tissue pathologies throughout the body. Lymphatic vessels play physiological roles relevant to all medical fields as important regulators of fluid balance, immune cell trafficking, and immune identity. Lymphangiogenesis is often concurrent with inflammation and can potentially aide or worsen disease progression. How new lymphatic vessels impact inflammation and by which mechanism is an important consideration in current and future clinical therapies targeting inflammation and/or vasculogenesis. This review identifies, across a range of tissue-specific pathologies, the current understanding of inflammation-associated lymphangiogenesis in the progression or resolution of inflammation.

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Macrophage alterations within the mesenteric lymphatic tissue are associated with impairment of lymphatic pump in metabolic syndrome

Cited by 36 publications

References 83 publications

Hyperglycemia‐ and hyperinsulinemia‐induced insulin resistance causes alterations in cellular bioenergetics and activation of inflammatory signaling in lymphatic muscle

Hyperglycemia‐ and hyperinsulinemia‐induced insulin resistance causes alterations in cellular bioenergetics and activation of inflammatory signaling in lymphatic muscle

Lymphatic Vessel Network Structure and Physiology

Lymphangiogenesis: fuel, smoke, or extinguisher of inflammation’s fire?

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