Macrophage-associated pro-inflammatory state in human islets from obese individuals

AbstractObesity is associated with inflammatory macrophages in insulin responsive tissues and the resulting inflammatory response is a major contributor to insulin resistance. In insulin-producing pancreatic islets, the intra-islet accumulation of macrophages is observed in patients of type 2 diabetes (T2D), but such has not been investigated in obese individuals. Here, we show that pro-inflammatory cytokines (IL-1β, IL-6, and TNF), anti-inflammatory cytokines (IL-10 and TGF-β) and macrophage polarization markers (CD11c, CD163, and NOS2) were expressed in isolated human islets from non-diabetic donors. Clodronate-mediated depletion of resident macrophages revealed expression of IL1B and IL10 mostly from macrophages, while IL6, TNF, and TGFB1 came largely from a non-macrophage origin in human islets. NOS2 expression came exclusively from non-macrophage cells in non-obese individuals, while it originated also from macrophages in obese donors. Macrophage marker expression of CD68, CD163, and ITGAX was unchanged in islets of non-obese control and obese cohorts. In contrast, IL1B and NOS2 were significantly increased in islets from obese, compared to non-obese individuals, implying a more inflammatory macrophage phenotype in islets in obesity. Our study shows elevated macrophage-associated inflammation in human islets in obesity, which could be an initiating factor to the pro-inflammatory intra-islet milieu and contribute to the higher susceptibility to T2D in obese individuals.

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Inhibition of SIK2 and SIK3 during differentiation enhances the anti-inflammatory phenotype of macrophages

Biochemical Journal ◽

10.1042/bcj20160646 ◽

2017 ◽

Vol 474 (4) ◽

pp. 521-537 ◽

Cited By ~ 18

Author(s):

Nicola J. Darling ◽

Rachel Toth ◽

J. Simon C. Arthur ◽

Kristopher Clark

Keyword(s):

Inflammatory Cytokines ◽

Drug Targets ◽

Macrophage Polarization ◽

Macrophage Phenotype ◽

Integral Role ◽

Inflammatory Phenotype ◽

Low Levels ◽

Anti Inflammatory ◽

Factor Α ◽

Pro Inflammatory Cytokines

The salt-inducible kinases (SIKs) control a novel molecular switch regulating macrophage polarization. Pharmacological inhibition of the SIKs induces a macrophage phenotype characterized by the secretion of high levels of anti-inflammatory cytokines, including interleukin (IL)-10, and the secretion of very low levels of pro-inflammatory cytokines, such as tumour necrosis factor α. The SIKs, therefore, represent attractive new drug targets for the treatment of macrophage-driven diseases, but which of the three isoforms, SIK1, SIK2 or SIK3, would be appropriate to target remains unknown. To address this question, we developed knock-in (KI) mice for SIK1, SIK2 and SIK3, in which we introduced a mutation that renders the enzymes catalytically inactive. Characterization of primary macrophages from the single and double KI mice established that all three SIK isoforms, and in particular SIK2 and SIK3, contribute to macrophage polarization. Moreover, we discovered that inhibition of SIK2 and SIK3 during macrophage differentiation greatly enhanced the production of IL-10 compared with their inhibition in mature macrophages. Interestingly, macrophages differentiated in the presence of SIK inhibitors, MRT199665 and HG-9-91-01, still produced very large amounts of IL-10, but very low levels of pro-inflammatory cytokines, even after the SIKs had been reactivated by removal of the drugs. Our data highlight an integral role for SIK2 and SIK3 in innate immunity by preventing the differentiation of macrophages into a potent and stable anti-inflammatory phenotype.

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Statins Directly Influence the Polarization of Adipose Tissue Macrophages: A Role in Chronic Inflammation

Biomedicines ◽

10.3390/biomedicines9020211 ◽

2021 ◽

Vol 9 (2) ◽

pp. 211

Author(s):

Sona Kauerova ◽

Hana Bartuskova ◽

Barbora Muffova ◽

Libor Janousek ◽

Jiri Fronek ◽

...

Keyword(s):

Adipose Tissue ◽

Ldl Cholesterol ◽

Macrophage Polarization ◽

Inflammatory Activity ◽

Human Macrophage ◽

Macrophage Phenotype ◽

Anti Inflammatory ◽

Inflammatory Macrophages ◽

Inflammatory Macrophage

Statins represent one of the most widely used classes of drugs in current medicine. In addition to a substantial decrease in atherogenic low density lipoprotein (LDL) particle concentrations, several large trials have documented their potent anti-inflammatory activity. Based on our preliminary data, we showed that statins are able to decrease the proportion of pro-inflammatory macrophages (CD14+16+CD36high) in visceral adipose tissue in humans. In the present study including 118 healthy individuals (living kidney donors), a very close relationship between the pro-inflammatory macrophage proportion and LDL cholesterol levels was found. This was confirmed after adjustment for the most important risk factors. The effect of statins on the proportion of pro-inflammatory macrophages was also confirmed in an experimental model of the Prague hereditary hypercholesterolemia rat. A direct anti-inflammatory effect of fluvastatin on human macrophage polarization in vitro was documented. Based on modifying the LDL cholesterol concentrations, statins are suggested to decrease the cholesterol inflow through the lipid raft of macrophages in adipose tissue and hypercholesterolemia to enhance the pro-inflammatory macrophage phenotype polarization. On the contrary, due to their opposite effect, statins respond with anti-inflammatory activity, affecting the whole organism.

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The Impact of Pro-Inflammatory Cytokines on Alternative Splicing Patterns in Human Islets

Diabetes ◽

10.2337/db20-0847 ◽

2021 ◽

pp. db200847

Author(s):

Wenting Wu ◽

Farooq Syed ◽

Edward Simpson ◽

Chih-Chun Lee ◽

Jing Liu ◽

...

Keyword(s):

Alternative Splicing ◽

Inflammatory Cytokines ◽

Human Islets ◽

The Impact ◽

Splicing Patterns ◽

Pro Inflammatory Cytokines

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Benznidazole Anti-Inflammatory Effects in Murine Cardiomyocytes and Macrophages Are Mediated by Class I PI3Kδ

Frontiers in Immunology ◽

10.3389/fimmu.2021.782891 ◽

2021 ◽

Vol 12 ◽

Author(s):

Ágata C. Cevey ◽

Paula D. Mascolo ◽

Federico N. Penas ◽

Azul V. Pieralisi ◽

Aldana S. Sequeyra ◽

...

Keyword(s):

Cell Line ◽

Chagas Disease ◽

Inflammatory Cytokines ◽

Immune Cells ◽

Macrophage Polarization ◽

Catalytic Subunit ◽

M2 Macrophage ◽

Socs3 Expression ◽

Anti Inflammatory ◽

Pro Inflammatory Cytokines

Benznidazole (Bzl), the drug of choice in many countries for the treatment of Chagas disease, leads to parasite clearance in the early stages of infection and contributes to immunomodulation. In addition to its parasiticidal effect, Bzl inhibits the NF-κB pathway. In this regard, we have previously described that this occurs through IL-10/STAT3/SOCS3 pathway. PI3K pathway is involved in the regulation of the immune system by inhibiting NF-κB pathway through STAT3. In this work, the participation of PI3K in the immunomodulatory effects of Bzl in cardiac and immune cells, the main targets of Chagas disease, was further studied. For that, we use a murine primary cardiomyocyte culture and a monocyte/macrophage cell line (RAW 264.7), stimulated with LPS in presence of LY294002, an inhibitor of PI3K. Under these conditions, Bzl could neither increase SOCS3 expression nor inhibit the NOS2 mRNA expression and the release of NOx, both in cardiomyocytes and macrophages. Macrophages are crucial in the development of Chronic Chagas Cardiomyopathy. Thus, to deepen our understanding of how Bzl acts, the expression profile of M1-M2 macrophage markers was evaluated. Bzl inhibited the release of NOx (M1 marker) and increased the expression of Arginase I (M2 marker) and a negative correlation was found between them. Besides, LPS increased the expression of pro-inflammatory cytokines. Bzl treatment not only inhibited this effect but also increased the expression of typical M2-macrophage markers like Mannose Receptor, TGF-β, and VEGF-A. Moreover, Bzl increased the expression of PPAR-γ and PPAR-α, known as key regulators of macrophage polarization. PI3K directly regulates M1-to-M2 macrophage polarization. Since p110δ, catalytic subunit of PI3Kδ, is highly expressed in immune cells, experiments were carried out in presence of CAL-101, a specific inhibitor of this subunit. Under this condition, Bzl could neither increase SOCS3 expression nor inhibit NF-κB pathway. Moreover, Bzl not only failed to inhibit the expression of pro-inflammatory cytokines (M1 markers) but also could not increase M2 markers. Taken together these results demonstrate, for the first time, that the anti-inflammatory effect of Bzl depends on PI3K activity in a cell line of murine macrophages and in primary culture of neonatal cardiomyocytes. Furthermore, Bzl-mediated increase expression of M2-macrophage markers involves the participation of the p110δ catalytic subunit of PI3Kδ.

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Glial Cells and Pro-inflammatory Cytokines as Shared Neurobiological Bases for Chronic Pain and Psychiatric Disorders

Overlapping Pain and Psychiatric Syndromes ◽

10.1093/med/9780190248253.003.0003 ◽

2020 ◽

pp. 27-49

Author(s):

Judith A. Strong ◽

Sang Won Jeon ◽

Jun-Ming Zhang ◽

Yong-Ku Kim

Keyword(s):

Chronic Pain ◽

Nervous System ◽

Psychiatric Disorders ◽

Inflammatory Cytokines ◽

Glial Cells ◽

Neuronal Excitability ◽

Pro Inflammatory Cytokines

This chapter reviews the roles of cytokines and glial cells in chronic pain and in psychiatric disorders, especially depression. One important role of cytokines is in communicating between activated glia and neurons, at all levels of the nervous system. This process of neuroinflammation plays important roles in pain and depression. Cytokines may also directly regulate neuronal excitability. Many cytokines have been implicated in both pain and psychiatric disorders, including interleukin-1β‎ (IL-1β‎), tumor necrosis factor-α‎, and IL-6. More generally, an imbalance between type 1, pro-inflammatory cytokines and type 2, anti-inflammatory cytokines has been implicated in both pain and psychiatric disorders. Activation of the sympathetic nervous system can contribute to both pain and psychiatric disorders, in part through its actions on inflammation and the cytokine profile.

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Author Correction: BCG and BCGΔBCG1419c protect type 2 diabetic mice against tuberculosis via different participation of T and B lymphocytes, dendritic cells and pro-inflammatory cytokines

npj Vaccines ◽

10.1038/s41541-020-00250-y ◽

2020 ◽

Vol 5 (1) ◽

Author(s):

Cristian Alfredo Segura-Cerda ◽

Brenda Marquina-Castillo ◽

Vasti Lozano-Ordaz ◽

Dulce Mata-Espinosa ◽

Jorge Alberto Barrios-Payán ◽

...

Keyword(s):

Dendritic Cells ◽

B Lymphocytes ◽

Inflammatory Cytokines ◽

T And B Lymphocytes ◽

Diabetic Mice ◽

Type 2 Diabetic ◽

Pro Inflammatory Cytokines

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

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Effect of Pro-inflammatory Cytokines on Expression and Activity of 11β-Hydroxysteroid Dehydrogenase Type 2 in Cultured Human Term Placental Trophoblast and Human Choriocarcinoma JEG-3 Cells

Journal of the Society for Gynecologic Investigation ◽

10.1016/j.jsgi.2005.02.003 ◽

2005 ◽

Vol 12 (5) ◽

pp. 303-309 ◽

Cited By ~ 23

Author(s):

Hiroshi Chisaka ◽

Jim F. Johnstone ◽

Manrina Premyslova ◽

Zuzka Manduch ◽

John R.G. Challis

Keyword(s):

Inflammatory Cytokines ◽

Hydroxysteroid Dehydrogenase ◽

Expression And Activity ◽

Pro Inflammatory Cytokines

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Cibinetide Protects Isolated Human Islets in a Stressful Environment and Improves Engraftment in the Perspective of Intra Portal Islet Transplantation

Cell Transplantation ◽

10.1177/09636897211039739 ◽

2021 ◽

Vol 30 ◽

pp. 096368972110397

Author(s):

Ming Yao ◽

Anna Domogatskaya ◽

Nils Ågren1 ◽

Masaaki Watanabe ◽

Kazuaki Tokodai ◽

...

Keyword(s):

Portal Vein ◽

Histological Examination ◽

Human Insulin ◽

Inflammatory Cytokines ◽

Caspase 3 ◽

Human Islets ◽

Human Islet ◽

Athymic Mice ◽

C Peptide ◽

Pro Inflammatory Cytokines

During intra-portal pancreatic islet transplantation (PITx), innate immune reactions such as the instant blood mediated inflammatory reaction (IBMIR) cause an immediate loss of islets. The non-hematopoietic erythropoietin analogue cibinetide has previously shown islet-protective effects in mouse PITx. Herein, we aimed to confirm cibinetide’s efficacy on human islets, and to characterize its effect on IBMIR. We cultured human islets with pro-inflammatory cytokines for 18 hours with or without cibinetide. ATP content and caspase 3/7 activity were measured. Dynamic glucose perfusion assay was used to evaluate islet function. To evaluate cibinetides effect on IBMIR, human islets were incubated in heparinized polyvinyl chloride tubing system with ABO compatible blood and rotated for 60 minutes to mimic the portal vein system. Moreover, human islets were transplanted into athymic mice livers via the portal vein with or without perioperative cibinetide treatment. The mice were sacrificed six days following transplantation and the livers were analyzed for human insulin and serum for human C-peptide levels. Histological examination of recipient livers to evaluate islet graft infiltration by CD11b+ cells was performed. Our results show that cibinetide maintained human islet ATP levels and reduced the caspase 3/7 activity during culture with pro-inflammatory cytokines and improved their insulin secreting capacity. In the PVC loop system, administration of cibinetide reduced the IBMIR-induced platelet consumption. In human islet to athymic mice PITx, cibinetide treatment showed an increased amount of human insulin in the livers and higher serum human C-peptide, while histological examination of the livers showed reduced infiltration of pro-inflammatory CD11b+ cells around islets grafts compared to the controls. In summary, Cibinetide protected isolated human islets in a pro-inflammatory milieu and reduced IBMIR related platelet consumption. It improved engraftment of human islets in athymic mice. The study confirms that cibinetide is a promising agent to be used in clinical PITx.

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