Cross-talk between B cells, microglia and macrophages, and implications to central nervous system compartmentalized inflammation and progressive multiple sclerosis.

CNS-compartmentalized inflammation Human B cells Human macrophage Human microglia Multiple sclerosis

Journal

EBioMedicine
ISSN: 2352-3964
Titre abrégé: EBioMedicine
Pays: Netherlands
ID NLM: 101647039

Informations de publication

Date de publication:
Oct 2023
Historique:
received: 14 02 2023
revised: 07 08 2023
accepted: 22 08 2023
pubmed: 14 9 2023
medline: 14 9 2023
entrez: 13 9 2023
Statut: ppublish

Résumé

B cells can be enriched within meningeal immune-cell aggregates of multiple sclerosis (MS) patients, adjacent to subpial cortical demyelinating lesions now recognized as important contributors to progressive disease. This subpial demyelination is notable for a 'surface-in' gradient of neuronal loss and microglial activation, potentially reflecting the effects of soluble factors secreted into the CSF. We previously demonstrated that MS B-cell secreted products are toxic to oligodendrocytes and neurons. The potential for B-cell-myeloid cell interactions to propagate progressive MS is of considerable interest. Secreted products of MS-implicated pro-inflammatory effector B cells or IL-10-expressing B cells with regulatory potential were applied to human brain-derived microglia or monocyte-derived macrophages, with subsequent assessment of myeloid phenotype and function through measurement of their expression of pro-inflammatory, anti-inflammatory and homeostatic/quiescent molecules, and phagocytosis (using flow cytometry, ELISA and fluorescently-labeled myelin). Effects of secreted products of differentially activated microglia on B-cell survival and activation were further studied. Secreted products of MS-implicated pro-inflammatory B cells (but not IL-10 expressing B cells) substantially induce pro-inflammatory cytokine (IL-12, IL-6, TNFα) expression by both human microglia and macrophage (in a GM-CSF dependent manner), while down-regulating their expression of IL-10 and of quiescence-associated molecules, and suppressing their myelin phagocytosis. In contrast, secreted products of IL-10 expressing B cells upregulate both human microglia and macrophage expression of quiescence-associated molecules and enhance their myelin phagocytosis. Secreted factors from pro-inflammatory microglia enhance B-cell activation. Potential cross-talk between disease-relevant human B-cell subsets and both resident CNS microglia and infiltrating macrophages may propagate CNS-compartmentalized inflammation and injury associated with MS disease progression. These interaction represents an attractive therapeutic target for agents such as Bruton's tyrosine kinase inhibitors (BTKi) that modulate responses of both B cells and myeloid cells. Stated in Acknowledgments section of manuscript.

Sections du résumé

BACKGROUND BACKGROUND
B cells can be enriched within meningeal immune-cell aggregates of multiple sclerosis (MS) patients, adjacent to subpial cortical demyelinating lesions now recognized as important contributors to progressive disease. This subpial demyelination is notable for a 'surface-in' gradient of neuronal loss and microglial activation, potentially reflecting the effects of soluble factors secreted into the CSF. We previously demonstrated that MS B-cell secreted products are toxic to oligodendrocytes and neurons. The potential for B-cell-myeloid cell interactions to propagate progressive MS is of considerable interest.
METHODS METHODS
Secreted products of MS-implicated pro-inflammatory effector B cells or IL-10-expressing B cells with regulatory potential were applied to human brain-derived microglia or monocyte-derived macrophages, with subsequent assessment of myeloid phenotype and function through measurement of their expression of pro-inflammatory, anti-inflammatory and homeostatic/quiescent molecules, and phagocytosis (using flow cytometry, ELISA and fluorescently-labeled myelin). Effects of secreted products of differentially activated microglia on B-cell survival and activation were further studied.
FINDINGS RESULTS
Secreted products of MS-implicated pro-inflammatory B cells (but not IL-10 expressing B cells) substantially induce pro-inflammatory cytokine (IL-12, IL-6, TNFα) expression by both human microglia and macrophage (in a GM-CSF dependent manner), while down-regulating their expression of IL-10 and of quiescence-associated molecules, and suppressing their myelin phagocytosis. In contrast, secreted products of IL-10 expressing B cells upregulate both human microglia and macrophage expression of quiescence-associated molecules and enhance their myelin phagocytosis. Secreted factors from pro-inflammatory microglia enhance B-cell activation.
INTERPRETATION CONCLUSIONS
Potential cross-talk between disease-relevant human B-cell subsets and both resident CNS microglia and infiltrating macrophages may propagate CNS-compartmentalized inflammation and injury associated with MS disease progression. These interaction represents an attractive therapeutic target for agents such as Bruton's tyrosine kinase inhibitors (BTKi) that modulate responses of both B cells and myeloid cells.
FUNDING BACKGROUND
Stated in Acknowledgments section of manuscript.

Identifiants

DOI: 10.1016/j.ebiom.2023.104789 PMID: 37703640 PMC: PMC10505984
pubmed: 37703640
pii: S2352-3964(23)00355-9
doi: 10.1016/j.ebiom.2023.104789
pmc: PMC10505984
pii:
doi:

Types de publication

Journal Article

Langues

eng

Sous-ensembles de citation

IM

Pagination

104789

Informations de copyright

Copyright © 2023 The Author(s). Published by Elsevier B.V. All rights reserved.

Déclaration de conflit d'intérêts

Declaration of interests H.T. and L.Z. received consulting fees from EMD Serono outside of the submitted work. D.J. has received consulting fees from Biogen, Genentech, Novartis, EMD Serono, Banner Life Sciences, Bristol Meyers Squibb, Horizon, Cycle and Sanofi Genzyme outside of the submitted work. A.BO. has received fees for advisory board participation and/or consulting from Abata, Accure, Atara Biotherapeutics, Biogen, BMS/Celgene/Receptos, GlaxoSmithKline, Gossamer, Immunic, Janssen/Actelion, Medimmune, Merck/EMD Serono, Novartis, Roche/Genentech, Sangamo, Sanofi-Genzyme, Viracta; and has received grant support to the University of Pennsylvania from Biogen Idec, Roche/Genentech, Merck/EMD Serono and Novartis. L.P. has recived grant support from Alector on projects not related to this work.

Auteurs

Hanane Touil (H)

Department of Neurology and Center for Neuroinflammation and Experimental Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.

Rui Li (R)

Department of Neurology and Center for Neuroinflammation and Experimental Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.

Leah Zuroff (L)

Department of Neurology and Center for Neuroinflammation and Experimental Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.

Craig S Moore (CS)

Division of BioMedical Sciences, Faculty of Medicine, Memorial University of Newfoundland, St. John's, NL, Canada.

Luke Healy (L)

Neuroimmunology Unit, Montréal Neurological Institute, McGill University, Canada.

Francesca Cignarella (F)

Department of Neurology, Washington University School of Medicine, 660 South Euclid Avenue, St Louis, MO, USA.

Laura Piccio (L)

Charles Perkins Centre and School of Medical Sciences, The University of Sydney, Camperdown, NSW, Australia.

Samuel Ludwin (S)

Department of Pathology and Molecular Medicine, Queen's University, Kingston, ON, K7L 3N6, Canada.

Alexandre Prat (A)

Université de Montréal Centre de Recherche du CHUM (CRCHUM) and Department of Neuroscience, Université de Montréal, 900 Saint Denis Street, Montréal, QC, H2X 0A9, Canada.

Jennifer Gommerman (J)

Department of Immunology, University of Toronto, Toronto, ON, M5S 1A8, Canada.

Frederick C Bennett (FC)

Department of Psychiatry, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.

Dina Jacobs (D)

Department of Neurology and Center for Neuroinflammation and Experimental Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.

Joyce A Benjamins (JA)

Departments of Neurology and Biochemistry, Immunology and Microbiology, Wayne State University School of Medicine, Detroit, MI, USA.

Robert P Lisak (RP)

Departments of Neurology and Biochemistry, Immunology and Microbiology, Wayne State University School of Medicine, Detroit, MI, USA.

Jack P Antel (JP)

Neuroimmunology Unit, Montréal Neurological Institute, McGill University, Canada.

Amit Bar-Or (A)

Department of Neurology and Center for Neuroinflammation and Experimental Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA. Electronic address: amitbar@pennmedicine.upenn.edu.

Classifications MeSH