Phosphatase regulation of macrophage activation

Kozicky, Lisa K.; Sly, Laura M.

doi:10.1016/j.smim.2015.07.001

Cited by 27 publications

(16 citation statements)

References 112 publications

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“…Several of these pathways are kinase dependent and regulated by phosphatases (192). The ubiquitous protein tyrosine phosphatase PTP1B has been shown to be integral to glucose and lipid metabolism in several tissues and control of energy and adiposity varies with the tissue location of PTP1B (193)(194)(195)(196)(197).…”

Section: Leukocyte Activation In Diabetes-what Is the Mechanism?mentioning

confidence: 99%

The Role of Inflammation in Diabetic Retinopathy

2020

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Inflammation is central to pathogenic processes in diabetes mellitus and the metabolic syndrome and particularly implicates innate immunity in the development of complications. Inflammation is a primary event in Type 1 diabetes where infectious (viral) and/or autoimmune processes initiate disease; in contrast, chronic inflammation is typical in Type 2 diabetes and is considered a sequel to increasing insulin resistance and disturbed glucose metabolism. Diabetic retinopathy (DR) is perceived as a vascular and neurodegenerative disease which occurs after some years of poorly controlled diabetes. However, many of the clinical features of DR are late events and reflect the nature of the retinal architecture and its cellular composition. Retinal microvascular disease is, in fact, an early event pathogenetically, induced by low grade, persistent leukocyte activation which causes repeated episodes of capillary occlusion and, progressive, attritional retinal ischemia. The later, overt clinical signs of DR are a consequence of the retinal ischemia. Metabolic dysregulation involving both lipid and glucose metabolism may lead to leukocyte activation. On a molecular level, we have shown that macrophage-restricted protein tyrosine phosphatase 1B (PTP1B) is a key regulator of inflammation in the metabolic syndrome involving insulin resistance and it is possible that PTP1B dysregulation may underlie retinal microvascular disease. We have also shown that adherent CCR5 + CD11b + monocyte macrophages appear to be selectively involved in retinal microvascular occlusion. In this review, we discuss the relationship between early leukocyte activation and the later features of DR, common pathogenetic processes between diabetic microvascular disease and other vascular retinopathies, the mechanisms whereby leukocyte activation is induced in hyperglycemia and dyslipidemia, the signaling mechanisms involved in diabetic microvascular disease, and possible interventions which may prevent these retinopathies. We also address a possible role for adaptive immunity in DR. Although significant improvements in treatment of DR have been made with intravitreal anti-VEGF therapy, a sizeable proportion of patients, particularly with sight-threatening macular edema, fail to respond. Alternative therapies targeting inflammatory processes may offer an advantage.

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Section: Leukocyte Activation In Diabetes-what Is the Mechanism?mentioning

confidence: 99%

The Role of Inflammation in Diabetic Retinopathy

2020

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“…In fact, many pro-inflammation pathways trigger the expression of certain anti-inflammatory molecules such as IL-10 [ 34 , 35 , 43 ]. Many phosphatases like PTEN phosphatase (PTP family) and MAP kinase phosphatases (MKPs) are major negative controls for inflammation while, at the same time, certain ubiquitin ligases function as inhibitory molecules for the inflammatory procedure [ 34 , 35 , 44 ]. Such an ubiquitin ligase is A20, a direct target gene for the NF-κB pathway and its action result in the downregulation of NF-κB activity [ 34 , 35 , 45 ].…”

Section: Telomeres Telomerase and Inflammation: An Introductionmentioning

confidence: 99%

The Telomere/Telomerase System in Chronic Inflammatory Diseases. Cause or Effect?

Kordinas

Ioannidis

Chatzipanagiotou

2016

Genes

116

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Telomeres are specialized nucleoprotein structures located at the end of linear chromosomes and telomerase is the enzyme responsible for telomere elongation. Telomerase activity is a key component of many cancer cells responsible for rapid cell division but it has also been found by many laboratories around the world that telomere/telomerase biology is dysfunctional in many other chronic conditions as well. These conditions are characterized by chronic inflammation, a situation mostly overlooked by physicians regarding patient treatment. Among others, these conditions include diabetes, renal failure, chronic obstructive pulmonary disease, etc. Since researchers have in many cases identified the association between telomerase and inflammation but there are still many missing links regarding this correlation, the latest findings about this phenomenon will be discussed by reviewing the literature. Our focus will be describing telomere/telomerase status in chronic diseases under the prism of inflammation, reporting molecular findings where available and proposing possible future approaches.

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“…Although kinases are critical in determining gene expression following cell activation, the protein phosphatases are equally important in dephosphorylating the activated signaling proteins thereby providing counter-regulation to avoid uncontrolled production of inflammatory cytokines/chemokines (5). Protein phosphatase 2A (PP2A), a key member of the Serine/Threonine Phosphatase family (6), is one of the phosphatases involved in negatively regulating the inflammatory response (7).…”

Section: Introductionmentioning

confidence: 99%

Myeloid-Specific Gene Deletion of Protein Phosphatase 2A Magnifies MyD88- and TRIF-Dependent Inflammation following Endotoxin Challenge

Sun

Pham

Cornell

et al. 2017

The Journal of Immunology

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Protein phosphatase 2A (PP2A) is a member of the intracellular serine/threonine (Ser/Thr) phosphatases. Innate immune cell activation triggered by pathogen-associated molecular patterns (PAMPs) is mediated by various protein kinases, and PP2A plays a counter regulatory role by deactivating these kinases. In this study, we generated a conditional knockout of the catalytic subunit of PP2A (PP2ACα). After crossing with myeloid-specific cre-expressing mice, effective gene knockout was achieved in various myeloid cells. The myeloid-specific knockout mice (lyM-PP2Afl/fl) showed higher mortality in response to both endotoxin challenge and bacterial infection. Upon LPS challenge, serum levels of TNF-α, KC, IL-6 and IL-10 were significantly increased in lyM-PP2Afl/fl mice and increased phosphorylation was observed in Mitogen Activated Protein Kinase (MAPK) pathways (p38, ERK, JNK) and the NF-κB pathway (IKKα/β, NF-κB p65) in bone marrow derived macrophages (BMDM) from knockout mice. Heightened NF-κB activation was not associated with degradation of IκB-α, instead, enhanced phosphorylation of the NF-κB p65 subunit and p38 phosphorylation-mediated TNF-α mRNA stabilization appear to contribute to the increased TNF-α expression. In addition, increased IL-10 expression appears to be due to PP2ACα knockout-induced IKKα/β hyper-activation. Microarray experiments indicated the TRIF/TRAF3 pathway was highly upregulated in LPS-treated PP2ACα knockout BMDM and knockout BMDM had elevated IFN-α/β production compared to control BMDM. Serum IFN-β levels from PP2ACα knockout mice treated with LPS was also greater than that in controls. Thus, we demonstrate that PP2A plays an important role in regulating inflammation and survival in the setting of septic insult, by targeting both MyD-88 and TRIF-dependent pathways.

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Phosphatase regulation of macrophage activation

Cited by 27 publications

References 112 publications

The Role of Inflammation in Diabetic Retinopathy

The Role of Inflammation in Diabetic Retinopathy

The Telomere/Telomerase System in Chronic Inflammatory Diseases. Cause or Effect?

Myeloid-Specific Gene Deletion of Protein Phosphatase 2A Magnifies MyD88- and TRIF-Dependent Inflammation following Endotoxin Challenge

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