A Physiological Function of Inflammation-Associated SerpinB2 Is Regulation of Adaptive Immunity

Schroder, Wayne A.; Le, Thuy T.; Major, Lee; Street, Shayna E.A.; Gardner, Joy; Lambley, Eleanore; Markey, Kate A.; MacDonald, Kelli Patricia; Fish, Richard J.; Thomas, Ranjeny; Suhrbier, Andreas

doi:10.4049/jimmunol.0902187

Cited by 106 publications

(123 citation statements)

References 66 publications

(60 reference statements)

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“…CHIKV infections induce a strongly Th1-biased immune response (10,11), with CCR2 Ϫ/Ϫ mice being reported to have impaired Th1 responses (20,40,41). However, analysis of anti-CHIKV IgG2c (Th1) and IgG1 (Th2) titers (32,42) illustrated that the dominant IgG2c responses were not significantly different in CCR2 Ϫ/Ϫ mice (Fig. 5A).…”

Section: Quantitation Of Histology and Immunohistochemistry Of Cellulmentioning

confidence: 99%

CCR2 Deficiency Promotes Exacerbated Chronic Erosive Neutrophil-Dominated Chikungunya Virus Arthritis

Poo

Nakaya

Gardner

et al. 2014

J Virol

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116

140

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Chikungunya virus (CHIKV) is a member of a globally distributed group of arthritogenic alphaviruses that cause weeks to months of debilitating polyarthritis/arthralgia, which is often poorly managed with current treatments. Arthritic disease is usually characterized by high levels of the chemokine CCL2 and a prodigious monocyte/macrophage infiltrate. Several inhibitors of CCL2 and its receptor CCR2 are in development and may find application for treatment of certain inflammatory conditions, including autoimmune and viral arthritides. Here we used CCR2 ؊/؊ mice to determine the effect of CCR2 deficiency on CHIKV infection and arthritis. Although there were no significant changes in viral load or RNA persistence and only marginal changes in antiviral immunity, arthritic disease was substantially increased and prolonged in CCR2 ؊/؊ mice compared to wild-type mice. The monocyte/macrophage infiltrate was replaced in CCR2 ؊/؊ mice by a severe neutrophil (followed by an eosinophil) infiltrate and was associated with changes in the expression levels of multiple inflammatory mediators (including CXCL1, CXCL2, granulocyte colony-stimulating factor [G-CSF], interleukin-1␤ [IL-1␤], and IL-10). The loss of anti-inflammatory macrophages and their activities (e.g., efferocytosis) was also implicated in exacerbated inflammation. Clear evidence of cartilage damage was also seen in CHIKV-infected CCR2 ؊/؊ mice, a feature not normally associated with alphaviral arthritides. Although recruitment of CCR2 ؉ monocytes/macrophages can contribute to inflammation, it also appears to be critical for preventing excessive pathology and resolving inflammation following alphavirus infection. Caution might thus be warranted when considering therapeutic targeting of CCR2/CCL2 for the treatment of alphaviral arthritides. IMPORTANCEHere we describe the first analysis of viral arthritis in mice deficient for the chemokine receptor CCR2. CCR2 is thought to be central to the monocyte/macrophage-dominated inflammatory arthritic infiltrates seen after infection with arthritogenic alphaviruses such as chikungunya virus. Surprisingly, the viral arthritis caused by chikungunya virus in CCR2-deficient mice was more severe, prolonged, and erosive and was neutrophil dominated, with viral replication and persistence not being significantly affected. Monocytes/macrophages recruited by CCL2 thus also appear to be important for both preventing even worse pathology mediated by neutrophils and promoting resolution of inflammation. Caution might thus be warranted when considering the use of therapeutic agents that target CCR2/CCL2 or inflammatory monocytes/macrophages for the treatment of alphaviral (and perhaps other viral) arthritides. Individuals with diminished CCR2 responses (due to drug treatment or other reasons) may also be at risk of exacerbated arthritic disease following alphaviral infection.

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Section: Quantitation Of Histology and Immunohistochemistry Of Cellulmentioning

confidence: 99%

CCR2 Deficiency Promotes Exacerbated Chronic Erosive Neutrophil-Dominated Chikungunya Virus Arthritis

Poo

Nakaya

Gardner

et al. 2014

J Virol

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116

140

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“…The ability of PAI-2 to inhibit the proteolytic activity of proteasome may explain the significance of this serpin for controlling the Th1-promoting cytokine production by macrophages. The phenotype of PAI-2 Ϫ/Ϫ macrophages, characterized by greater IFN-␥ secretion when compared with normal macrophages, was mapped to enhanced CD40 and NF-B signaling (39). Because both CD40 and IB␣ are natural substrates of proteasome, it is reasonable to predict that PAI-2, by interaction with proteasome, can protect them from degradation, thereby promoting signaling pathways in which these proteins participate.…”

Section: Discussionmentioning

confidence: 99%

Association of Plasminogen Activator Inhibitor Type 2 (PAI-2) with Proteasome within Endothelial Cells Activated with Inflammatory Stimuli

Boncela

Przygodzka

Papiewska-Pająk

et al. 2011

Journal of Biological Chemistry

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Quiescent endothelial cells contain low concentrations of plasminogen activator inhibitor type 2 (PAI-2). However, its synthesis can be rapidly stimulated by a variety of inflammatory mediators. In this study, we provide evidence that PAI-2 interacts with proteasome and affects its activity in endothelial cells. To ensure that the PAI-2⅐proteasome complex is formed in vivo, both proteins were coimmunoprecipitated from endothelial cells and identified with specific antibodies. The specificity of this interaction was evidenced after (a) transfection of HeLa cells with pCMV-PAI-2 and coimmunoprecipitation of both proteins with anti-PAI-2 antibodies and (b) silencing of the PAI-2 gene using specific small interfering RNA (siRNA). Subsequently, cellular distribution of the PAI-2⅐proteasome complexes was established by immunogold staining and electron microscopy analyses. As judged by confocal microscopy, both proteins appeared in a diffuse cytosolic pattern, but they also could be found in a dense perinuclear and nuclear location. PAI-2 was not polyubiquitinated, suggesting that it bound to proteasome not as the substrate but rather as its inhibitor. Consistently, increased PAI-2 expression (a) abrogated degradation of degron analyzed after cotransfection of HeLa cells with pCMV-PAI-2 and pd2EGFP-N1, (b) prevented degradation of p53, as evidenced both by confocal microscopy and Western immunoblotting, and (c) inhibited proteasome cleavage of specific fluorogenic substrate. This suggests that PAI-2, in endothelial cells induced with inflammatory stimuli, can inhibit proteasome and thus tilt the balance favoring proapoptotic signaling. Plasminogen activator inhibitor type-2 (PAI-2)2 has both extracellular and intracellular functions and acts as a multifunctional protein (1, 2). It exists predominantly as a 47-kDa nonglycosylated intracellular form (3). Due to the lack of an N-terminal signal peptide, only a small percentage of PAI-2 is exported from cells, by the nonclassical secretory pathway, as a glycosylated 60-kDa form (4). PAI-2 contains a unique domain bridging helices C and D, called the C-D loop (5), which directly interacts with different proteins, including retinoblastoma protein (6), proteasome subunit member ␤1 (7), interferon response factor 3 (8), ZNF198/FGFR1 fusion kinase (9), annexins (10), pre-mRNA processing factor 8 (7), and vitronectin (11).The primary physiological function of PAI-2 is thought to be the regulation of plasminogen activators in the extravascular compartment (1, 12). However, such a role is not supported by studies using PAI-2 Ϫ/Ϫ mice that show no discernable defects in fibrinolysis (13). Covalent PAI-2⅐uPA complexes, readily formed in vitro, have also never been unequivocally demonstrated in vivo (14). On the other hand, PAI-2 has been proposed to play a role in different processes, including tumor metastasis, embryo implantation, and macrophage survival (1, 2, 15). Consistently, a broad range of activities were ascribed to PAI-2, such as protection of the retinoblastoma protein f...

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“…The enhanced noncovalent binding of PZP to PP14 (a lipocalin) is likely to be the result of hydrophobic interactions. Experiments in PAI-2 knockout mice indicate that PAI-2 also plays a role in Th1 cell suppression (Schroder et al, 2010). The mechanism by which this is achieved is not known, but appears to be unrelated to PAI-2 protease inhibitory activity and could involve intracellular functions (Fig.…”

Section: Disease Implicationsmentioning

confidence: 99%

“…This includes modulation of T-cell responses (Schroder et al, 2010) and stabilisation of misfolded proteins similar to holdase-type chaperones (Lee et al, 2015) (Fig. 2).…”

Section: Biological Functionmentioning

confidence: 99%

PZP and PAI-2: Structurally-diverse, functionally similar pregnancy proteins?

Wyatt

Cater

Ranson

2016

The International Journal of Biochemistry & Cell Biology

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Pregnancy zone protein (PZP) and plasminogen activator inhibitor type 2 (PAI-2) are two multifunctional proteins that are elevated in normal pregnancy and numerous other inflammatory states. Both proteins were originally identified as protease inhibitors, but current evidence supports the notion that they may also function as modulators of T-helper cells and/or extracellular chaperones. Exacerbated inflammation, fibrinolytic disturbances and misfolded proteins are all implicated in the pathology of preeclampsia, a leading cause of maternal and foetal mortality and morbidity. Notably, reduced levels of PZP or PAI-2 are associated with preeclampsia and clarification of their diverse functions in normal pregnancy could provide much needed insight regarding the pathogenesis of this disorder. Given that inflammation and protein misfolding underlie the pathology of a very large number of disorders, the contributions of PZP and PAI-2 to extracellular proteostasis and immunoregulation could be broad-reaching. Given that inflammation and protein misfolding underlie the pathology of a very large number of disorders, the contributions of PZP and PAI-2 to extracellular proteostasis and immunoregulation could be broad-reaching.

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A Physiological Function of Inflammation-Associated SerpinB2 Is Regulation of Adaptive Immunity

Abstract: Material Supplementary 7.DC1http://www.jimmunol.org/content/suppl/2010/02/01/jimmunol.090218

Cited by 106 publications

References 66 publications

CCR2 Deficiency Promotes Exacerbated Chronic Erosive Neutrophil-Dominated Chikungunya Virus Arthritis

CCR2 Deficiency Promotes Exacerbated Chronic Erosive Neutrophil-Dominated Chikungunya Virus Arthritis

Association of Plasminogen Activator Inhibitor Type 2 (PAI-2) with Proteasome within Endothelial Cells Activated with Inflammatory Stimuli

PZP and PAI-2: Structurally-diverse, functionally similar pregnancy proteins?

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