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Multiple Sclerosis Patient Macrophages Impaired Metabolism Leads to an Altered Response to Activation Stimuli
Jennifer Fransson1, Corinne Bachelin1, Farid Ichou1
1From the Sorbonne Université (J.F., C.B., L.G.-N., E.M., A.T., F.M., C.L., V.Z.), Institut du Cerveau - Paris Brain Institute - ICM, Inserm, CNRS, APHP, Hôpital Pitié Salpétrière Univ. Hosp., DMU Neuroscience 6; Inst. of Cardiometabolism and Nutrition (F.I., M.P.), Sorbonne-universités-Upmc 06, INSERM, CNRS; Laboratoire des Signaux et Systèmes (L2S) (A.G., A.T.), CNRS-CentraleSupélec, Université Paris-Saclay; Sorbonne Université (B.S.), Institut du Cerveau - Paris Brain Institute - ICM, Inserm, CNRS, APHP, Hôpital St. Antoine-HUEP; and INSERM (B.F.), SU, AP-HP, Centre de recherche en Myologie-UMR974 and Service of Neuro-Myology, Institute of Myology, University hospital Pitié-Salpêtriere.
Background And Objectives:
In multiple sclerosis (MS), immune cells invade the CNS and destroy myelin. Macrophages contribute to demyelination and myelin repair, and their role in each process depends on their ability to acquire specific phenotypes in response to external signals. In this article, we assess whether defects in MS patient macrophage responses may lead to increased inflammation or lack of neuroregenerative effects.
Methods:
CD14+CD16- monocytes from patients with MS and healthy controls (HCs) were activated in vitro to obtain homeostatic-like, proinflammatory, and proregenerative macrophages. Macrophage activation profiles were assessed through RNA sequencing and metabolomics. Surface molecule expression of CD14, CD16, and HLA-DR and myelin phagocytic capacity were evaluated with flow cytometry. Macrophage supernatant capacity to influence oligodendrocyte precursor cell differentiation toward an astrocytic or oligodendroglia fate was also tested.
Results:
We observed that MS patient monocytes ex vivo recapitulate their preferential activation toward the CD16+ phenotype, a subset of proinflammatory cells overrepresented in MS lesions. Functionally, MS patient macrophages display a decreased capacity to phagocytose human myelin and a deficit of processing myelin after ingestion. In addition, MS patient macrophage supernatant favors astrocytes over oligodendrocyte differentiation when compared with HC macrophage supernatant. Furthermore, even when exposed to homeostatic or proregenerative stimuli, MS patient macrophages uphold a proinflammatory transcriptomic profile with higher levels of cytokine/chemokine. Of interest, MS patient macrophages exhibit a distinct metabolic signature with a mitochondrial energy metabolism blockage. Transcriptomic data are further substantiated by metabolomics studies that reveal perturbations in the corresponding metabolic pathways.
Discussion:
Our results show an intrinsic defect of MS patient macrophages, reminiscent of innate immune cell memory in MS, lifting macrophage importance in the disease and as potential therapeutic targets.
Insights
Multiple sclerosis (MS) patient macrophages show defects in myelin processing and promote inflammation. These findings highlight intrinsic macrophage dysfunction in MS and suggest them as potential therapeutic targets.
Area of Science:
- Neuroimmunology
- Cellular Biology
- Metabolomics
Background:
- Multiple sclerosis (MS) involves immune cell invasion of the central nervous system (CNS), leading to myelin destruction.
- Macrophages play a dual role in demyelination and myelin repair, influenced by their phenotype.
- Understanding macrophage dysfunction in MS is crucial for identifying therapeutic strategies.
Purpose of the Study:
- To investigate potential defects in macrophage responses in MS patients.
- To determine if these defects contribute to increased inflammation or impaired neuroregeneration in MS.
- To explore the functional and metabolic profiles of macrophages from MS patients.
Main Methods:
- Monocytes from MS patients and healthy controls (HCs) were differentiated into macrophages in vitro.
- RNA sequencing and metabolomics were used to assess macrophage activation profiles.
- Flow cytometry evaluated surface markers and myelin phagocytosis; supernatant effects on oligodendrocyte precursor cells were tested.
Main Results:
- MS patient macrophages preferentially adopted a proinflammatory CD16+ phenotype, overrepresented in MS lesions.
- MS macrophages exhibited reduced myelin phagocytosis and impaired myelin processing.
- MS macrophage supernatant favored astrocytic differentiation over oligodendroglial differentiation.
- MS macrophages maintained a proinflammatory transcriptomic profile and showed mitochondrial energy metabolism defects.
Conclusions:
- MS patient macrophages possess intrinsic defects, suggesting a role for innate immune cell memory in MS.
- These findings underscore the significance of macrophages as potential therapeutic targets in MS.
- Defective macrophage function in MS contributes to neuroinflammation and hinders repair mechanisms.
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