Acute phase protein, α – 1- acid glycoprotein (AGP-1), has differential effects on TLR-2 and TLR-4 mediated responses

Sumanth, Mosale Seetharam; Abhilasha, Kandahalli Venkataranganayaka; Jacob, Shancy Petsel; Chaithra, Vyala Hanumanthareddy; Basrur, Venkatesha; Willard, Belinda; McIntyre, Thomas M.; Prabhu, K. Sandeep; Marathe, Gopal K.

doi:10.1101/634295

Cited by 4 publications

(16 citation statements)

References 41 publications

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“…To define this, we first defined relevant functions for AGP-1 in the inflammatory system. AGP-1-induces Ca 2+ influx in neutrophils (35,36) to activate these cells (24). In accordance with our previous data, sAGP-1-induces concentration-dependent activation of neutrophil adhesion and migration.…”

Section: Discussionsupporting

confidence: 91%

“…4 A, B inset). sAGP-1 suppressed LPS-induced inflammatory responses (24), and sAGP-1, but not nAGP-1, inhibited LPS-induced NETosis in a concentration-dependent fashion ( Fig. 5).…”

Section: Sagp-1 Induces Neutrophil Extracellular Traps (Netosis) Whilmentioning

confidence: 84%

“…We previously observed that serum AGP-1 preferentially inhibits the TLR-4 agonist bacterial lipopolysaccharide (LPS), but not TLR-2 agonist Braun Lipoprotein (BLP) mediated inflammatory responses both in vivo and in vitro (24,25). We now show that the hepatocytederived serum AGP-1 (sAGP-1) is proinflammatory, while the neutrophil derived glycoforms (nAGP-1) primarily display antiinflammatory activity.…”

Section: Introductionmentioning

confidence: 81%

“…Although AGP-1 levels are elevated during inflammation, its biological function(s) remain obscure. We previously purified serum AGP-1 (sAGP-1, 43 kDa) to explore its differential effects on TLR-2 and TLR-4 mediated inflammatory responses in vivo and in vitro (24). As there are more than 150 glycoforms of AGP-1 present in the human plasma, this could add to the complexity of AGP-1 biology (2,8,13,14,17).…”

Section: Discussionmentioning

confidence: 99%

“…The ratio of the two isoforms differed according to the inciting agonists. We sought to purify the higher molecular weight nAGP-1 isoform using conventional chromatographic techniques (Methods) (24) and so stimulated neutrophils with PAF to obtain an AGP-1 corresponding to sAGP-1 and nAGP-1. However, only the larger nAGP-1 was isolated by this purification protocol and was used for further experimentations (Fig.…”

Section: Neutrophils Secrete Distinct Agp-1 Isoformsmentioning

confidence: 99%

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Differential glycosylation of alpha-1-acid glycoprotein (AGP-1) contributes to its functional diversity

Sumanth

Jacob

Abhilasha

et al. 2020

Preprint

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Alpha-1-acid glycoprotein (AGP-1) is a positive acute phase glycoprotein with uncertain functions. Serum AGP-1 (sAGP-1) is primarily derived from hepatocytes and circulates as 12 to 20 different glycoforms. We isolated a glycoform secreted from stimulated human neutrophils (nAGP-1). Its peptide sequence was identical to hepatocyte-derived sAGP-1, but nAGP-1 differed from sAGP-1 in its chromatographic behaviour, electrophoretic mobility, and glycosylation. The function of these two glycoforms also differed. sAGP-1 activated neutrophil adhesion, migration and NETosis in a dose-dependent fashion, while nAGP-1 was ineffective as an agonist for these events. Furthermore, sAGP-1, but not nAGP-1, inhibited LPS-stimulated NETosis. However, nAGP-1 inhibited sAGP-1-stimulated neutrophil NETosis. The discordant effect of the differentially glycosylated AGP-1 glycoforms was also observed in platelets where neither of the AGP-1 glycoforms alone stimulated aggregation of washed human platelets, but sAGP-1, and not nAGP-1, inhibited aggregation induced by Platelet-activating Factor (PAF) or ADP, but not by thrombin. These functional effects of sAGP-1 correlated with intracellular cAMP accumulation and were accompanied by phosphorylation of the PKA substrate Vasodialator stimulated phosphoprotein (VASP) and reduction of Akt, ERK, and p38 phosphorylation. Thus, the sAGP-1 glycoform limits platelet reactivity while nAGP-1 glycoform also limits pro-inflammatory actions of sAGP-1. These studies identify new functions for this acute phase glycoprotein and demonstrate that the glycosylation of AGP-1 controls its effects on two critical cells of acute inflammation.

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Section: Discussionsupporting

confidence: 91%

“…4 A, B inset). sAGP-1 suppressed LPS-induced inflammatory responses (24), and sAGP-1, but not nAGP-1, inhibited LPS-induced NETosis in a concentration-dependent fashion ( Fig. 5).…”

Section: Sagp-1 Induces Neutrophil Extracellular Traps (Netosis) Whilmentioning

confidence: 84%

Section: Introductionmentioning

confidence: 81%

Section: Discussionmentioning

confidence: 99%

Section: Neutrophils Secrete Distinct Agp-1 Isoformsmentioning

confidence: 99%

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Differential glycosylation of alpha-1-acid glycoprotein (AGP-1) contributes to its functional diversity

Sumanth

Jacob

Abhilasha

et al. 2020

Preprint

Self Cite

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Different glycoforms of alpha-1-acid glycoprotein contribute to its functional alterations in platelets and neutrophils

Sumanth

Jacob

Abhilasha

et al. 2020

Journal of Leukocyte Biology

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Alpha-1-acid glycoprotein (AGP-1) is a positive acute phase glycoprotein with uncertain functions.Serum AGP-1 (sAGP-1) is primarily derived from hepatocytes and circulates as 12-20 different glycoforms. We isolated a glycoform secreted from platelet-activating factor (PAF)-stimulated human neutrophils (nAGP-1). Its peptide sequence was identical to hepatocyte-derived sAGP-1, but nAGP-1 differed from sAGP-1 in its chromatographic behavior, electrophoretic mobility, and pattern of glycosylation. The function of these 2 glycoforms also differed. sAGP-1 activated neutrophil adhesion, migration, and neutrophil extracellular traps (NETosis) involving myeloperoxidase, peptidylarginine deiminase 4, and phosphorylation of ERK in a dose-dependent fashion, whereas nAGP-1 was ineffective as an agonist for these events. Furthermore, sAGP-1, but not nAGP-1, inhibited LPS-stimulated NETosis. Interestingly, nAGP-1 inhibited sAGP-1-stimulated neutrophil NETosis. The discordant effect of the differentially glycosylated AGP-1 glycoforms was also observed in platelets where neither of the AGP-1 glycoforms alone stimulated aggregation of washed human platelets, but sAGP-1, and not nAGP-1, inhibited aggregation induced by PAF or ADP, but not by thrombin. These functional effects of sAGP-1 correlated with intracellular cAMP accumulation and phosphorylation of the protein kinase A substrate vasodilator-stimulated phosphoprotein and reduction of Akt, ERK, and p38 phosphorylation. Thus, the sAGP-1 glycoform limits platelet reactivity, whereas nAGP-1 glycoform also limits proinflammatory actions of sAGP-1. These studies identify new functions for this acute phase glycoprotein and demonstrate that the glycosylation of AGP-1 controls its effects on 2 critical cells of acute inflammation.

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α1-Acid glycoprotein and seminal parameter in chronic hemodialysis patients

et al. 2020

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Introduction: To find out the changes in seminal quality of hemodialysis chronic renal patients, we investigated the possible relationship between seminal parameter and seminal α1-acid glycoprotein levels in chronic hemodialysis patients. Methods: Prospective study of prevalence realized in the Hemodialysis Sector of the University Hospital of the University of Brasília, between July 2016 and December 2016. Men aged 18–60 years grouped into case groups (n = 81) represented by chronic hemodialysis patients and control group (n = 20) of healthy men without clinical or laboratory signs of infection and eugonadic. We performed a spermogram, hormonal profile, and assessment of leukocytes and seminal α1-acid glycoprotein level in the semen. The most appropriate statistical test was applied to verify differences and correlations between the studied variables. Results: The age in case and control is similar (49.47 ± 5.55 years vs 50.53 ± 4.24 years; p = 0.060). Mean level of α1-acid glycoprotein in human seminal plasma were not significantly different between case and control (48.52 ± 4.90 mg/L vs 46.33 ± 4.29 mg/L; p = 0.10) and between normosperm and oligosperm (47.76 ± 5.15 mg/L vs 49.48 ± 4.49 mg/L; p = 0.19). Mean level of α1-acid glycoprotein in human seminal plasma in the case group, which were classified into severe, moderate, mild, and normosperm, were similar to each other (p = 0.27) and did not correlate (p > 0.05) with the analyzed seminal parameters. All participants presented normal hormonal profile. Conclusion: Results of this study suggest that the seminal α1-acid glycoprotein levels do not help in the initial evaluation of patients with seminal parameter changes.

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Acute phase protein, α – 1- acid glycoprotein (AGP-1), has differential effects on TLR-2 and TLR-4 mediated responses

Cited by 4 publications

References 41 publications

Differential glycosylation of alpha-1-acid glycoprotein (AGP-1) contributes to its functional diversity

Differential glycosylation of alpha-1-acid glycoprotein (AGP-1) contributes to its functional diversity

Different glycoforms of alpha-1-acid glycoprotein contribute to its functional alterations in platelets and neutrophils

α1-Acid glycoprotein and seminal parameter in chronic hemodialysis patients

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