C-Reactive Protein Promotes Inflammation through FcγR-Induced Glycolytic Reprogramming of Human Macrophages

Newling, Melissa; Sritharan, Lathees; Ham, Alwin J. van der; Hoepel, Willianne; Fiechter, R.; Boer, Leonie de; Zaat, Sebastian A. J.; Bisoendial, Radjesh J; Baeten, Dominique; Everts, Bart; Dunnen, Jeroen den

doi:10.4049/jimmunol.1900172

Cited by 34 publications

(36 citation statements)

References 61 publications

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“…In both T1D and T2D, dysregulated glucose and lipid metabolism drive the chronic inflammatory state which manifests with increased levels of inflammatory biomarkers and acute phase reactants ( 29 , 49 , 50 ). Some such as C-reactive protein (CRP) and triglyceride-rich lipoproteins exert a direct pro-inflammatory effect by activating blood monocytes ( 20 , 51 ).…”

Section: Is Inflammation In Diabetes a Direct Or An Indirect Cause Ofmentioning

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: Is Inflammation In Diabetes a Direct Or An Indirect Cause Ofmentioning

confidence: 99%

The Role of Inflammation in Diabetic Retinopathy

2020

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“…When macrophages encounter CRP-opsonized bacteria, both PRRs and FcγRs will be stimulated simultaneously. Similar to IgG, bacterial opsonization with CRP results in a synergistic up-regulation of pro-inflammatory cytokines TNF, IL-1β, IL-6, and IL-23 by human PBMCs [ 82 ] and pro-inflammatory macrophages [ 93 ]. The modulated cytokine profile by FcR-TLR cross-talk skews Th cell responses towards Th17, which thereby tailors immune responses to counteract extracellular bacterial infections.…”

Section: Physiological Immune Activation: Host Defense Against Pathogensmentioning

confidence: 99%

Physiological and Pathological Inflammation Induced by Antibodies and Pentraxins

Geyer

Mes

Newling

et al. 2021

Cells

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Macrophages play a key role in induction of inflammatory responses. These inflammatory responses are mostly considered to be instigated by activation of pattern recognition receptors (PRRs) or cytokine receptors. However, recently it has become clear that also antibodies and pentraxins, which can both activate Fc receptors (FcRs), induce very powerful inflammatory responses by macrophages that can even be an order of magnitude greater than PRRs. While the physiological function of this antibody-dependent inflammation (ADI) is to counteract infections, undesired activation or over-activation of this mechanism will lead to pathology, as observed in a variety of disorders, including viral infections such as COVID-19, chronic inflammatory disorders such as Crohn’s disease, and autoimmune diseases such as rheumatoid arthritis. In this review we discuss how physiological ADI provides host defense by inducing pathogen-specific immunity, and how erroneous activation of this mechanism leads to pathology. Moreover, we will provide an overview of the currently known signaling and metabolic pathways that underlie ADI, and how these can be targeted to counteract pathological inflammation.

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“…The blockage of glycoprotein IIb-IIIa on activated platelets prevents dissociation of native CRP to mCRP reducing the arterial platelet deposition (de la Torre et al, 2013). The binding of mCRP to phosphorylcholine on activated macrophage and foam cell membranes mediated by concomitant Fcγ receptor and toll-like receptor signaling (Newling et al, 2019) and the presence of mCRP within advanced atherosclerotic plaques seem to play a critical role in the development and progression of a plaque by promoting inflammation, oxidation, smooth muscle cell proliferation, and migration and thrombus formation (Figure 1).…”

Section: Thrombosis and Inflammation And C-reactive Protein Isoformsmentioning

confidence: 99%

Thrombogenic and Inflammatory Reactions to Biomaterials in Medical Devices

Labarrere

Dabiri

Kassab

2020

Front. Bioeng. Biotechnol.

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Blood-contacting medical devices of different biomaterials are often used to treat various cardiovascular diseases. Thrombus formation is a common cause of failure of cardiovascular devices. Currently, there are no clinically available biomaterials that can totally inhibit thrombosis under the more challenging environments (e.g., low flow in the venous system). Although some biomaterials reduce protein adsorption or cell adhesion, the issue of biomaterial associated with thrombosis and inflammation still exists. To better understand how to develop more thrombosis-resistant medical devices, it is essential to understand the biology and mechano-transduction of thrombus nucleation and progression. In this review, we will compare the mechanisms of thrombus development and progression in the arterial and venous systems. We will address various aspects of thrombosis, starting with biology of thrombosis, mathematical modeling to integrate the mechanism of thrombosis, and thrombus formation on medical devices. Prevention of these problems requires a multifaceted approach that involves more effective and safer thrombolytic agents but more importantly the development of novel thrombosis-resistant biomaterials mimicking the biological characteristics of the endothelium and extracellular matrix tissues that also ameliorate the development and the progression of chronic inflammation as part of the processes associated with the detrimental generation of late thrombosis and neo-atherosclerosis. Until such developments occur, engineers and clinicians must work together to develop devices that require minimal anticoagulants and thrombolytics to mitigate thrombosis and inflammation without causing serious bleeding side effects.

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C-Reactive Protein Promotes Inflammation through FcγR-Induced Glycolytic Reprogramming of Human Macrophages

Cited by 34 publications

References 61 publications

The Role of Inflammation in Diabetic Retinopathy

The Role of Inflammation in Diabetic Retinopathy

Physiological and Pathological Inflammation Induced by Antibodies and Pentraxins

Thrombogenic and Inflammatory Reactions to Biomaterials in Medical Devices

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