The immunoproteasome controls the availability of the cardioprotective pattern recognition molecule Pentraxin3

Paeschke, Anna; Possehl, Anna; Klingel, Karin; Voß, Martin; Voss, Karolin; Kespohl, Meike; Sauter, Martina; Overkleeft, Hermen S.; Althof, Nadine; Garlanda, Cecília; Voigt, Antje

doi:10.1002/eji.201545892

Cited by 27 publications

(52 citation statements)

References 59 publications

(102 reference statements)

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“…PTX3 synthesis and production following cellular activation by LPS is mediated by the transcription factors nuclear factor (NF)-kB and activator protein 1 (AP-1). [9][10][11] Consequently, PTX3 has been shown to serve as a counter-regulatory protein which inhibits pro-inflammatory signaling, 5 protects the hosts from inflammatory damage of the heart (i.e. reduced lesion size within the coronary artery and aorta), 12,13 and improves survival from toxic shock caused by LPS in vivo.…”

Section: Introductionmentioning

confidence: 99%

Exercise reduced pentraxin 3 levels produced by endotoxin-stimulated human peripheral blood mononuclear cells in obese individuals

Slusher

Shibata

Whitehurst

et al. 2017

Exp Biol Med (Maywood)

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Impact statementOur laboratory has previously demonstrated that obese individuals present with lower plasma concentrations of the antiinflammatory protein pentraxin 3 (PTX3), whereas acute aerobic exercise increases plasma PTX3 levels similarly compared to normal-weight individuals. As a follow-up, the present study demonstrates that PBMCs isolated from obese and normalweight individuals produce comparable amounts of PTX3 ex vivo in response to lipopolysaccharide (LPS). Furthermore, given that acute aerobic exercise reduced the ex vivo production of PTX3 in both groups, our results clearly indicate that plasma PTX3 levels are relatively independent of those produced by PBMCs ex vivo. In addition, our findings suggest that the mechanisms associated with PTX3-mediated production of the anti-inflammatory cytokine interleukin 10 may be impaired in obese individuals, and thus provides a key finding necessary for the elucidation of PTX3's role in the mediation of anti-inflammatory profiles and the subsequent amelioration of inflammatory disease during obesity. AbstractThe purpose of this study was to determine whether obesity would reduce the capacity of peripheral blood mononuclear cells (PBMCs) to produce the anti-inflammatory protein pentraxin 3 (PTX3) in response to ex vivo stimulation with lipopolysaccharide (LPS), and if acute aerobic exercise would enhance this PTX3 production capacity. In addition, the inter-relationships of LPS-induced PTX3 with the inflammatory cytokines (interleukin 6 [IL-6], IL-10, and tumor necrosis factor alpha) were examined. Twenty-one healthy subjects (10 obese and 11 normal-weight) performed an acute bout of aerobic exercise at 75% VO 2max . The capacity of PBMCs to produce PTX3 ex vivo following LPS stimulation was the same in obese and normal-weight subjects at rest, and decreased equally in both subject groups following acute aerobic exercise. This is in contrast to plasma PTX3, which is lower in obese subjects at rest and increased equally in both obese and normal-weight subjects following exercise. In addition, ex vivo PTX3 production was positively associated with IL-6 and IL-10 in response to acute aerobic exercise (r ¼ 0.686, P ¼ 0.020; r ¼ 0.744, P ¼ 0.009, respectively) in normal-weight, but not in obese individuals (r ¼ 0.429, P ¼ 0.249; r ¼ 0.453, P ¼ 0.189, respectively). These findings indicate that concentrations of PTX3 observed in plasma are relatively independent of those produced by PBMCs ex vivo and the mechanisms associated with PTX3-mediated anti-inflammatory signaling may differ during obesity.

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Section: Introductionmentioning

confidence: 99%

Exercise reduced pentraxin 3 levels produced by endotoxin-stimulated human peripheral blood mononuclear cells in obese individuals

Slusher

Shibata

Whitehurst

et al. 2017

Exp Biol Med (Maywood)

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“…Nevertheless, in vitro findings on PA28α/β function were not corroborated by in vivo infection studies that investigated CVB3 myocarditis in constitutive PA28α/β -/- mice. Other than reported for cytokine-inducible immunoproteasome formation [29, 31], PA28α/β is most likely not a prerequisite for coping with CVB3 myocarditis in C57BL/6 mice.…”

Section: Discussionmentioning

confidence: 79%

“…Mouse bone marrow-derived macrophages (BMMs) were isolated by flushing the femur and tibiae with pre-warmed RPMI 1640 medium (Biochrom) and cultured according to the methods described recently [31]. BMMs were used after approximately eight days of culture.…”

Section: Methodsmentioning

confidence: 99%

“…CVB3 infection was conducted in eCM and HeLa cells at a multiplicity of infection (MOI) of 0.01 or 0.1 as recently described [31]. For all in vitro assays on cell viability, BMMs were stimulated with polyinosinic:polycytidylic (poly-I:C) acid (50 μg/ml, Invivogen).…”

Section: Methodsmentioning

confidence: 99%

“…Substantial in vitro evidence was provided for facilitated antigen processing by such ip particles during CVB3 infection [5, 6, 30] and ablation of LMP7 in mice resulted in aggravated myocardial inflammation [29] putatively involving ip-dependent pentraxin3 expression [31]. Nevertheless, the abundance and function of IFN-γ-inducible PA28α/β complexes is still enigmatic during viral myocarditis.…”

Section: Introductionmentioning

confidence: 99%

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PA28 modulates antigen processing and viral replication during coxsackievirus B3 infection

et al. 2017

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The function of the proteasome is modulated at the level of subunit expression and by association with its regulatory complexes. During coxsackievirus B3 (CVB3) myocarditis, IFN-induced formation of immunoproteasomes (ip) is known to be critical for regulating immune modulating molecules. The function of the IFN-γ-inducible proteasome regulator subunits PA28 α and β, however, in this context was unknown. During viral myocarditis, we found an increased abundance of PA28β subunits in heart tissue. PA28α/β exists in PA28-20S-PA28 and PA700-20S-PA28 hybrid proteasome complexes in cells both with either predominant ip and standard proteasome (sp) expression. Being in line with reduced proteasome activity in PA28α/β-deficient cells, we observed increased levels of oxidized and poly-ubiquitinated proteins upon TLR3-activation in these cells. Moreover, PA28α/β is capable to interfere directly with viral replication of CVB3 and facilitates the generation of CVB3-derived MHC class I epitopes by the proteasome. In contrast to a distinct function of PA28α/β in vitro, gene ablation of PA28α/β in mice being on a genetic background with resistance towards the development of severe infection had no significant impact on disease progression. Other than reported for the ip, in this host PA28α/β is dispensable to meet the demand of increased peptide hydrolysis capacity by the proteasome during viral myocarditis.

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An overview of the immune mechanisms of viral myocarditis

Lasrado

Reddy

2020

Reviews in Medical Virology

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Viral myocarditis has been identified as a major cause of dilated cardiomyopathy (DCM) that can lead to heart failure. Historically, Coxsackieviruses and adenoviruses have been commonly suspected in myocarditis/DCM patients in North America and Europe. However, this notion is changing as other viruses such as Parvovirus B19 and human herpesvirus-6 are increasingly reported as causes of myocarditis in the United States, with the most recent example being the severe acute respiratory syndrome coronavirus 2, causing the Coronavirus Disease-19. The mouse model of Coxsackievirus B3 (CVB3)-induced myocarditis, which may involve mediation of autoimmunity, is routinely used in the study of immune pathogenesis of viral infections as triggers of DCM. In this review, we discuss the immune mechanisms underlying the development of viral myocarditis with an emphasis on autoimmunity in the development of post-infectious myocarditis induced with CVB3.

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The immunoproteasome controls the availability of the cardioprotective pattern recognition molecule Pentraxin3

Cited by 27 publications

References 59 publications

Exercise reduced pentraxin 3 levels produced by endotoxin-stimulated human peripheral blood mononuclear cells in obese individuals

Exercise reduced pentraxin 3 levels produced by endotoxin-stimulated human peripheral blood mononuclear cells in obese individuals

PA28 modulates antigen processing and viral replication during coxsackievirus B3 infection

An overview of the immune mechanisms of viral myocarditis

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