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Matrix Metalloproteinase-9-Generated COOH-, but Not NH(2)-Terminal Fragments of Serum Amyloid A1 Retain Potentiating Activity in Neutrophil Migration to CXCL8, With Loss of Direct Chemotactic and Cytokine-Inducing Capacity
Serum amyloid A1 (SAA1) is a prototypic acute phase protein, induced to extremely high levels by physical insults, including inflammation and infection. Human SAA and its NH(2)-terminal part have been studied extensively in the context of amyloidosis. By contrast, little is known about COOH-terminal...
Autores principales: | , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Frontiers Media S.A.
2018
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5994419/ https://www.ncbi.nlm.nih.gov/pubmed/29915572 http://dx.doi.org/10.3389/fimmu.2018.01081 |
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author | Gouwy, Mieke De Buck, Mieke Abouelasrar Salama, Sara Vandooren, Jennifer Knoops, Sofie Pörtner, Noëmie Vanbrabant, Lotte Berghmans, Nele Opdenakker, Ghislain Proost, Paul Van Damme, Jo Struyf, Sofie |
author_facet | Gouwy, Mieke De Buck, Mieke Abouelasrar Salama, Sara Vandooren, Jennifer Knoops, Sofie Pörtner, Noëmie Vanbrabant, Lotte Berghmans, Nele Opdenakker, Ghislain Proost, Paul Van Damme, Jo Struyf, Sofie |
author_sort | Gouwy, Mieke |
collection | PubMed |
description | Serum amyloid A1 (SAA1) is a prototypic acute phase protein, induced to extremely high levels by physical insults, including inflammation and infection. Human SAA and its NH(2)-terminal part have been studied extensively in the context of amyloidosis. By contrast, little is known about COOH-terminal fragments of SAA. Intact SAA1 chemoattracts leukocytes via the G protein-coupled receptor formyl peptide receptor like 1/formyl peptide receptor 2 (FPR2). In addition to direct leukocyte activation, SAA1 induces chemokine production by signaling through toll-like receptor 2. We recently discovered that these induced chemokines synergize with intact SAA1 to chemoattract leukocytes in vitro and in vivo. Gelatinase B or matrix metalloproteinase-9 (MMP-9) is also induced by SAA1 during infection and inflammation and processes many substrates in the immune system. We demonstrate here that MMP-9 rapidly cleaves SAA1 at a known consensus sequence that is also present in gelatins. Processing of SAA1 by MMP-9 at an accessible loop between two alpha helices yielded predominantly three COOH-terminal fragments: SAA1(52–104), SAA1(57–104), and SAA1(58–104), with a relative molecular mass of 5,884.4, 5,327.3, and 5,256.3, respectively. To investigate the effect of proteolytic processing on the biological activity of SAA1, we chemically synthesized the COOH-terminal SAA fragments SAA1(52–104) and SAA1(58–104) and the complementary NH(2)-terminal peptide SAA1(1–51). In contrast to intact SAA1, the synthesized SAA1 peptides did not induce interleukin-8/CXCL8 in monocytes or fibroblasts. Moreover, these fragments possessed no direct chemotactic activity for neutrophils, as observed for intact SAA1. However, comparable to intact SAA1, SAA1(58–104) cooperated with CXCL8 in neutrophil activation and migration, whereas SAA1(1–51) lacked this potentiating activity. This cooperative interaction between the COOH-terminal SAA1 fragment and CXCL8 in neutrophil chemotaxis was mediated by FPR2. Hence, proteolytic cleavage of SAA1 by MMP-9 fine tunes the inflammatory capacity of this acute phase protein in that only the synergistic interactions with chemokines remain to prolong the duration of inflammation. |
format | Online Article Text |
id | pubmed-5994419 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2018 |
publisher | Frontiers Media S.A. |
record_format | MEDLINE/PubMed |
spelling | pubmed-59944192018-06-18 Matrix Metalloproteinase-9-Generated COOH-, but Not NH(2)-Terminal Fragments of Serum Amyloid A1 Retain Potentiating Activity in Neutrophil Migration to CXCL8, With Loss of Direct Chemotactic and Cytokine-Inducing Capacity Gouwy, Mieke De Buck, Mieke Abouelasrar Salama, Sara Vandooren, Jennifer Knoops, Sofie Pörtner, Noëmie Vanbrabant, Lotte Berghmans, Nele Opdenakker, Ghislain Proost, Paul Van Damme, Jo Struyf, Sofie Front Immunol Immunology Serum amyloid A1 (SAA1) is a prototypic acute phase protein, induced to extremely high levels by physical insults, including inflammation and infection. Human SAA and its NH(2)-terminal part have been studied extensively in the context of amyloidosis. By contrast, little is known about COOH-terminal fragments of SAA. Intact SAA1 chemoattracts leukocytes via the G protein-coupled receptor formyl peptide receptor like 1/formyl peptide receptor 2 (FPR2). In addition to direct leukocyte activation, SAA1 induces chemokine production by signaling through toll-like receptor 2. We recently discovered that these induced chemokines synergize with intact SAA1 to chemoattract leukocytes in vitro and in vivo. Gelatinase B or matrix metalloproteinase-9 (MMP-9) is also induced by SAA1 during infection and inflammation and processes many substrates in the immune system. We demonstrate here that MMP-9 rapidly cleaves SAA1 at a known consensus sequence that is also present in gelatins. Processing of SAA1 by MMP-9 at an accessible loop between two alpha helices yielded predominantly three COOH-terminal fragments: SAA1(52–104), SAA1(57–104), and SAA1(58–104), with a relative molecular mass of 5,884.4, 5,327.3, and 5,256.3, respectively. To investigate the effect of proteolytic processing on the biological activity of SAA1, we chemically synthesized the COOH-terminal SAA fragments SAA1(52–104) and SAA1(58–104) and the complementary NH(2)-terminal peptide SAA1(1–51). In contrast to intact SAA1, the synthesized SAA1 peptides did not induce interleukin-8/CXCL8 in monocytes or fibroblasts. Moreover, these fragments possessed no direct chemotactic activity for neutrophils, as observed for intact SAA1. However, comparable to intact SAA1, SAA1(58–104) cooperated with CXCL8 in neutrophil activation and migration, whereas SAA1(1–51) lacked this potentiating activity. This cooperative interaction between the COOH-terminal SAA1 fragment and CXCL8 in neutrophil chemotaxis was mediated by FPR2. Hence, proteolytic cleavage of SAA1 by MMP-9 fine tunes the inflammatory capacity of this acute phase protein in that only the synergistic interactions with chemokines remain to prolong the duration of inflammation. Frontiers Media S.A. 2018-06-04 /pmc/articles/PMC5994419/ /pubmed/29915572 http://dx.doi.org/10.3389/fimmu.2018.01081 Text en Copyright © 2018 Gouwy, De Buck, Abouelasrar Salama, Vandooren, Knoops, Pörtner, Vanbrabant, Berghmans, Opdenakker, Proost, Van Damme and Struyf. https://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms. |
spellingShingle | Immunology Gouwy, Mieke De Buck, Mieke Abouelasrar Salama, Sara Vandooren, Jennifer Knoops, Sofie Pörtner, Noëmie Vanbrabant, Lotte Berghmans, Nele Opdenakker, Ghislain Proost, Paul Van Damme, Jo Struyf, Sofie Matrix Metalloproteinase-9-Generated COOH-, but Not NH(2)-Terminal Fragments of Serum Amyloid A1 Retain Potentiating Activity in Neutrophil Migration to CXCL8, With Loss of Direct Chemotactic and Cytokine-Inducing Capacity |
title | Matrix Metalloproteinase-9-Generated COOH-, but Not NH(2)-Terminal Fragments of Serum Amyloid A1 Retain Potentiating Activity in Neutrophil Migration to CXCL8, With Loss of Direct Chemotactic and Cytokine-Inducing Capacity |
title_full | Matrix Metalloproteinase-9-Generated COOH-, but Not NH(2)-Terminal Fragments of Serum Amyloid A1 Retain Potentiating Activity in Neutrophil Migration to CXCL8, With Loss of Direct Chemotactic and Cytokine-Inducing Capacity |
title_fullStr | Matrix Metalloproteinase-9-Generated COOH-, but Not NH(2)-Terminal Fragments of Serum Amyloid A1 Retain Potentiating Activity in Neutrophil Migration to CXCL8, With Loss of Direct Chemotactic and Cytokine-Inducing Capacity |
title_full_unstemmed | Matrix Metalloproteinase-9-Generated COOH-, but Not NH(2)-Terminal Fragments of Serum Amyloid A1 Retain Potentiating Activity in Neutrophil Migration to CXCL8, With Loss of Direct Chemotactic and Cytokine-Inducing Capacity |
title_short | Matrix Metalloproteinase-9-Generated COOH-, but Not NH(2)-Terminal Fragments of Serum Amyloid A1 Retain Potentiating Activity in Neutrophil Migration to CXCL8, With Loss of Direct Chemotactic and Cytokine-Inducing Capacity |
title_sort | matrix metalloproteinase-9-generated cooh-, but not nh(2)-terminal fragments of serum amyloid a1 retain potentiating activity in neutrophil migration to cxcl8, with loss of direct chemotactic and cytokine-inducing capacity |
topic | Immunology |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5994419/ https://www.ncbi.nlm.nih.gov/pubmed/29915572 http://dx.doi.org/10.3389/fimmu.2018.01081 |
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