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

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

doi:10.1016/j.ebiom.2023.104789

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

EBioMedicine. 2023 Oct:96:104789. doi: 10.1016/j.ebiom.2023.104789. Epub 2023 Sep 11.

Authors

Affiliations

¹ Department of Neurology and Center for Neuroinflammation and Experimental Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
² Division of BioMedical Sciences, Faculty of Medicine, Memorial University of Newfoundland, St. John's, NL, Canada.
³ Neuroimmunology Unit, Montréal Neurological Institute, McGill University, Canada.
⁴ Department of Neurology, Washington University School of Medicine, 660 South Euclid Avenue, St Louis, MO, USA.
⁵ Charles Perkins Centre and School of Medical Sciences, The University of Sydney, Camperdown, NSW, Australia.
⁶ Department of Pathology and Molecular Medicine, Queen's University, Kingston, ON, K7L 3N6, Canada.
⁷ 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.
⁸ Department of Immunology, University of Toronto, Toronto, ON, M5S 1A8, Canada.
⁹ Department of Psychiatry, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
¹⁰ Departments of Neurology and Biochemistry, Immunology and Microbiology, Wayne State University School of Medicine, Detroit, MI, USA.
¹¹ 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.

Abstract

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.

Keywords: CNS-compartmentalized inflammation; Human B cells; Human macrophage; Human microglia; Multiple sclerosis.