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Complement activation and increased anaphylatoxin receptor expression are associated with cortical grey matter lesions and the compartmentalised inflammatory response of multiple sclerosis

Rhian Evans, Lewis Watkins, Kristen Hawkins, Gabriella Santiago, Constantinos Demetriou, Michelle Naughton, Marie Dittmer, Mark I. Rees, Denise Fitzgerald, B. Paul Morgan, James Neal, Owain Howell Orcid Logo

Frontiers in Cellular Neuroscience, Volume: 17

Swansea University Authors: Rhian Evans, Lewis Watkins, Kristen Hawkins, Gabriella Santiago, Constantinos Demetriou, James Neal, Owain Howell Orcid Logo

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DOI (Published version): 10.3389/fncel.2023.1094106

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Background: The extent of cortical pathology is an important determinant of multiple sclerosis (MS) severity. Cortical demyelination and neurodegeneration are related to inflammation of the overlying leptomeninges, a more inflammatory CSF milieu and with parenchymal microglia and astroglia activatio...

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Published in: Frontiers in Cellular Neuroscience
ISSN: 1662-5102
Published: Frontiers Media SA 2023
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Cortical demyelination and neurodegeneration are related to inflammation of the overlying leptomeninges, a more inflammatory CSF milieu and with parenchymal microglia and astroglia activation. These are all components of the compartmentalised inflammatory response. Compartmentalised inflammation is a feature of progressive MS, which is not targeted by disease modifying therapies. Complement is differentially expressed in the MS CSF and complement, and complement receptors, are associated with demyelination and neurodegeneration. Methods: To better understand if complement activation in the leptomeninges is associated with underlying cortical demyelination, inflammation, and microglial activation, we performed a neuropathological study of progressive MS (n = 22, 14 females), neuroinflammatory (n = 8), and non-neurological disease controls (n = 10). We then quantified the relative extent of demyelination, connective tissue inflammation, complement, and complement receptor positive microglia/macrophages. Results: Complement was elevated at the leptomeninges, subpial, and within and around vessels of the cortical grey matter. The extent of complement C1q immunoreactivity correlated with connective tissue infiltrates, whilst activation products C4d, Bb, and C3b associated with grey matter demyelination, and C3a receptor 1+ and C5a receptor 1+ microglia/macrophages closely apposed C3b labelled cells. The density of C3a receptor 1+ and C5a receptor 1+ cells was increased at the expanding edge of subpial and leukocortical lesions. C5a receptor 1+ cells expressed TNFα, iNOS and contained puncta immunoreactive for proteolipid protein, neurofilament and synaptophysin, suggesting their involvement in grey matter lesion expansion. Interpretation: The presence of products of complement activation at the brain surfaces, their association with the extent of underlying pathology and increased complement anaphylatoxin receptor positive microglia/macrophages at expanding cortical grey matter lesions, could represent a target to modify compartmentalised inflammation and cortical demyelination.</abstract><type>Journal Article</type><journal>Frontiers in Cellular Neuroscience</journal><volume>17</volume><journalNumber/><paginationStart/><paginationEnd/><publisher>Frontiers Media SA</publisher><placeOfPublication/><isbnPrint/><isbnElectronic/><issnPrint/><issnElectronic>1662-5102</issnElectronic><keywords>Complement, demyelination, leptomeninges, microglia, inflammation</keywords><publishedDay>22</publishedDay><publishedMonth>3</publishedMonth><publishedYear>2023</publishedYear><publishedDate>2023-03-22</publishedDate><doi>10.3389/fncel.2023.1094106</doi><url>http://dx.doi.org/10.3389/fncel.2023.1094106</url><notes/><college>COLLEGE NANME</college><department>Biomedical Sciences</department><CollegeCode>COLLEGE CODE</CollegeCode><DepartmentCode>BMS</DepartmentCode><institution>Swansea University</institution><apcterm>Other</apcterm><funders>This work was supported by funds from the MacDaid Fellowship, Worshipful Livery Company of Wales, the Life Science Research Network Wales, the UK Multiple Sclerosis Society, and the Research Wales Innovation Fund and the BRAIN Unit Infrastructure Award (Grant no: UA05; funded by Welsh Government through Health and Care Research Wales).</funders><projectreference/><lastEdited>2024-01-08T13:49:43.9892109</lastEdited><Created>2023-07-06T13:29:09.3591864</Created><path><level id="1">Faculty of Medicine, Health and Life Sciences</level><level id="2">Swansea University Medical School - Biomedical Science</level></path><authors><author><firstname>Rhian</firstname><surname>Evans</surname><order>1</order></author><author><firstname>Lewis</firstname><surname>Watkins</surname><orcid/><order>2</order></author><author><firstname>Kristen</firstname><surname>Hawkins</surname><order>3</order></author><author><firstname>Gabriella</firstname><surname>Santiago</surname><order>4</order></author><author><firstname>Constantinos</firstname><surname>Demetriou</surname><order>5</order></author><author><firstname>Michelle</firstname><surname>Naughton</surname><order>6</order></author><author><firstname>Marie</firstname><surname>Dittmer</surname><order>7</order></author><author><firstname>Mark I.</firstname><surname>Rees</surname><order>8</order></author><author><firstname>Denise</firstname><surname>Fitzgerald</surname><order>9</order></author><author><firstname>B. 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spelling v2 63788 2023-07-06 Complement activation and increased anaphylatoxin receptor expression are associated with cortical grey matter lesions and the compartmentalised inflammatory response of multiple sclerosis 9972a14ebece936662244293596faae8 Rhian Evans Rhian Evans true false 255b8c16eb0ed44b6a3f85f584916bc3 Lewis Watkins Lewis Watkins true false e49e8a552ec24b278bee246db3f8d8a8 Kristen Hawkins Kristen Hawkins true false 9fed0ec56118efb2fb777d1aff1f8c5b Gabriella Santiago Gabriella Santiago true false 93ba010da6a6b4496c518badb4f418cf Constantinos Demetriou Constantinos Demetriou true false 3d905ecd4df7a2ee050a8804c1140de1 James Neal James Neal true false 58c995486fc93a242b987640b692db8c 0000-0003-2157-9157 Owain Howell Owain Howell true false 2023-07-06 BMS Background: The extent of cortical pathology is an important determinant of multiple sclerosis (MS) severity. Cortical demyelination and neurodegeneration are related to inflammation of the overlying leptomeninges, a more inflammatory CSF milieu and with parenchymal microglia and astroglia activation. These are all components of the compartmentalised inflammatory response. Compartmentalised inflammation is a feature of progressive MS, which is not targeted by disease modifying therapies. Complement is differentially expressed in the MS CSF and complement, and complement receptors, are associated with demyelination and neurodegeneration. Methods: To better understand if complement activation in the leptomeninges is associated with underlying cortical demyelination, inflammation, and microglial activation, we performed a neuropathological study of progressive MS (n = 22, 14 females), neuroinflammatory (n = 8), and non-neurological disease controls (n = 10). We then quantified the relative extent of demyelination, connective tissue inflammation, complement, and complement receptor positive microglia/macrophages. Results: Complement was elevated at the leptomeninges, subpial, and within and around vessels of the cortical grey matter. The extent of complement C1q immunoreactivity correlated with connective tissue infiltrates, whilst activation products C4d, Bb, and C3b associated with grey matter demyelination, and C3a receptor 1+ and C5a receptor 1+ microglia/macrophages closely apposed C3b labelled cells. The density of C3a receptor 1+ and C5a receptor 1+ cells was increased at the expanding edge of subpial and leukocortical lesions. C5a receptor 1+ cells expressed TNFα, iNOS and contained puncta immunoreactive for proteolipid protein, neurofilament and synaptophysin, suggesting their involvement in grey matter lesion expansion. Interpretation: The presence of products of complement activation at the brain surfaces, their association with the extent of underlying pathology and increased complement anaphylatoxin receptor positive microglia/macrophages at expanding cortical grey matter lesions, could represent a target to modify compartmentalised inflammation and cortical demyelination. Journal Article Frontiers in Cellular Neuroscience 17 Frontiers Media SA 1662-5102 Complement, demyelination, leptomeninges, microglia, inflammation 22 3 2023 2023-03-22 10.3389/fncel.2023.1094106 http://dx.doi.org/10.3389/fncel.2023.1094106 COLLEGE NANME Biomedical Sciences COLLEGE CODE BMS Swansea University Other This work was supported by funds from the MacDaid Fellowship, Worshipful Livery Company of Wales, the Life Science Research Network Wales, the UK Multiple Sclerosis Society, and the Research Wales Innovation Fund and the BRAIN Unit Infrastructure Award (Grant no: UA05; funded by Welsh Government through Health and Care Research Wales). 2024-01-08T13:49:43.9892109 2023-07-06T13:29:09.3591864 Faculty of Medicine, Health and Life Sciences Swansea University Medical School - Biomedical Science Rhian Evans 1 Lewis Watkins 2 Kristen Hawkins 3 Gabriella Santiago 4 Constantinos Demetriou 5 Michelle Naughton 6 Marie Dittmer 7 Mark I. Rees 8 Denise Fitzgerald 9 B. Paul Morgan 10 James Neal 11 Owain Howell 0000-0003-2157-9157 12 63788__28277__67e3ef55b0564151a656f8e0f24ea0ff.pdf 63788.VOR.pdf 2023-08-09T10:04:42.5033812 Output 9576833 application/pdf Version of Record true © 2023 Evans, Watkins, Hawkins, Santiago, Demetriou, Naughton, Dittmer, Rees, Fitzgerald, Morgan, Neal and Howell. Distributed under the terms of a Creative Commons Attribution 4.0 License (CC BY 4.0). true eng https://creativecommons.org/licenses/by/4.0/
title Complement activation and increased anaphylatoxin receptor expression are associated with cortical grey matter lesions and the compartmentalised inflammatory response of multiple sclerosis
spellingShingle Complement activation and increased anaphylatoxin receptor expression are associated with cortical grey matter lesions and the compartmentalised inflammatory response of multiple sclerosis
Rhian Evans
Lewis Watkins
Kristen Hawkins
Gabriella Santiago
Constantinos Demetriou
James Neal
Owain Howell
title_short Complement activation and increased anaphylatoxin receptor expression are associated with cortical grey matter lesions and the compartmentalised inflammatory response of multiple sclerosis
title_full Complement activation and increased anaphylatoxin receptor expression are associated with cortical grey matter lesions and the compartmentalised inflammatory response of multiple sclerosis
title_fullStr Complement activation and increased anaphylatoxin receptor expression are associated with cortical grey matter lesions and the compartmentalised inflammatory response of multiple sclerosis
title_full_unstemmed Complement activation and increased anaphylatoxin receptor expression are associated with cortical grey matter lesions and the compartmentalised inflammatory response of multiple sclerosis
title_sort Complement activation and increased anaphylatoxin receptor expression are associated with cortical grey matter lesions and the compartmentalised inflammatory response of multiple sclerosis
author_id_str_mv 9972a14ebece936662244293596faae8
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9fed0ec56118efb2fb777d1aff1f8c5b
93ba010da6a6b4496c518badb4f418cf
3d905ecd4df7a2ee050a8804c1140de1
58c995486fc93a242b987640b692db8c
author_id_fullname_str_mv 9972a14ebece936662244293596faae8_***_Rhian Evans
255b8c16eb0ed44b6a3f85f584916bc3_***_Lewis Watkins
e49e8a552ec24b278bee246db3f8d8a8_***_Kristen Hawkins
9fed0ec56118efb2fb777d1aff1f8c5b_***_Gabriella Santiago
93ba010da6a6b4496c518badb4f418cf_***_Constantinos Demetriou
3d905ecd4df7a2ee050a8804c1140de1_***_James Neal
58c995486fc93a242b987640b692db8c_***_Owain Howell
author Rhian Evans
Lewis Watkins
Kristen Hawkins
Gabriella Santiago
Constantinos Demetriou
James Neal
Owain Howell
author2 Rhian Evans
Lewis Watkins
Kristen Hawkins
Gabriella Santiago
Constantinos Demetriou
Michelle Naughton
Marie Dittmer
Mark I. Rees
Denise Fitzgerald
B. Paul Morgan
James Neal
Owain Howell
format Journal article
container_title Frontiers in Cellular Neuroscience
container_volume 17
publishDate 2023
institution Swansea University
issn 1662-5102
doi_str_mv 10.3389/fncel.2023.1094106
publisher Frontiers Media SA
college_str Faculty of Medicine, Health and Life Sciences
hierarchytype
hierarchy_top_id facultyofmedicinehealthandlifesciences
hierarchy_top_title Faculty of Medicine, Health and Life Sciences
hierarchy_parent_id facultyofmedicinehealthandlifesciences
hierarchy_parent_title Faculty of Medicine, Health and Life Sciences
department_str Swansea University Medical School - Biomedical Science{{{_:::_}}}Faculty of Medicine, Health and Life Sciences{{{_:::_}}}Swansea University Medical School - Biomedical Science
url http://dx.doi.org/10.3389/fncel.2023.1094106
document_store_str 1
active_str 0
description Background: The extent of cortical pathology is an important determinant of multiple sclerosis (MS) severity. Cortical demyelination and neurodegeneration are related to inflammation of the overlying leptomeninges, a more inflammatory CSF milieu and with parenchymal microglia and astroglia activation. These are all components of the compartmentalised inflammatory response. Compartmentalised inflammation is a feature of progressive MS, which is not targeted by disease modifying therapies. Complement is differentially expressed in the MS CSF and complement, and complement receptors, are associated with demyelination and neurodegeneration. Methods: To better understand if complement activation in the leptomeninges is associated with underlying cortical demyelination, inflammation, and microglial activation, we performed a neuropathological study of progressive MS (n = 22, 14 females), neuroinflammatory (n = 8), and non-neurological disease controls (n = 10). We then quantified the relative extent of demyelination, connective tissue inflammation, complement, and complement receptor positive microglia/macrophages. Results: Complement was elevated at the leptomeninges, subpial, and within and around vessels of the cortical grey matter. The extent of complement C1q immunoreactivity correlated with connective tissue infiltrates, whilst activation products C4d, Bb, and C3b associated with grey matter demyelination, and C3a receptor 1+ and C5a receptor 1+ microglia/macrophages closely apposed C3b labelled cells. The density of C3a receptor 1+ and C5a receptor 1+ cells was increased at the expanding edge of subpial and leukocortical lesions. C5a receptor 1+ cells expressed TNFα, iNOS and contained puncta immunoreactive for proteolipid protein, neurofilament and synaptophysin, suggesting their involvement in grey matter lesion expansion. Interpretation: The presence of products of complement activation at the brain surfaces, their association with the extent of underlying pathology and increased complement anaphylatoxin receptor positive microglia/macrophages at expanding cortical grey matter lesions, could represent a target to modify compartmentalised inflammation and cortical demyelination.
published_date 2023-03-22T13:49:45Z
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score 11.013686

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