Cross-talk between B cells, microglia and macrophages, and implications to central nervous system compartmentalized inflammation and progressive multiple sclerosisResearch in context
Hanane Touil,
Rui Li,
Leah Zuroff,
Craig S. Moore,
Luke Healy,
Francesca Cignarella,
Laura Piccio,
Samuel Ludwin,
Alexandre Prat,
Jennifer Gommerman,
Frederick C. Bennett,
Dina Jacobs,
Joyce A. Benjamins,
Robert P. Lisak,
Jack P. Antel,
Amit Bar-Or
Affiliations
Hanane Touil
Department of Neurology and Center for Neuroinflammation and Experimental Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
Rui Li
Department of Neurology and Center for Neuroinflammation and Experimental Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
Leah Zuroff
Department of Neurology and Center for Neuroinflammation and Experimental Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
Craig S. Moore
Division of BioMedical Sciences, Faculty of Medicine, Memorial University of Newfoundland, St. John's, NL, Canada
Luke Healy
Neuroimmunology Unit, Montréal Neurological Institute, McGill University, Canada
Francesca Cignarella
Department of Neurology, Washington University School of Medicine, 660 South Euclid Avenue, St Louis, MO, USA
Laura Piccio
Charles Perkins Centre and School of Medical Sciences, The University of Sydney, Camperdown, NSW, Australia
Samuel Ludwin
Department of Pathology and Molecular Medicine, Queen's University, Kingston, ON, K7L 3N6, Canada
Alexandre Prat
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
Department of Immunology, University of Toronto, Toronto, ON, M5S 1A8, Canada
Frederick C. Bennett
Department of Psychiatry, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
Dina Jacobs
Department of Neurology and Center for Neuroinflammation and Experimental Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
Joyce A. Benjamins
Departments of Neurology and Biochemistry, Immunology and Microbiology, Wayne State University School of Medicine, Detroit, MI, USA
Robert P. Lisak
Departments of Neurology and Biochemistry, Immunology and Microbiology, Wayne State University School of Medicine, Detroit, MI, USA
Jack P. Antel
Neuroimmunology Unit, Montréal Neurological Institute, McGill University, Canada
Amit Bar-Or
Department of Neurology and Center for Neuroinflammation and Experimental Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA; Corresponding author. The Center for Neuroinflammation and Experimental Therapeutics and the Department of Neurology, Hospital of the University of Pennsylvania, Philadelphia, PA, 19204, USA.
Summary: 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: 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: 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: 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: Stated in Acknowledgments section of manuscript.
