member

Research work

Multiple sclerosis (MS) is an inflammatory, neurodegenerative disease in which infiltration of immune cells in the central nervous system (CNS) leads to myelin destruction. But immune cells can also participate to the myelin repair process by orchestrating the activation, recruitment and differentiation of new myelin forming cells.

Our group aim to describe how macrophages and lymphocytes defects contribute to MS pathology.

1. To understand lymphocyte role in remyelination, we developed a humanized mouse model of remyelination by grafting healthy control or MS patient lymphocyte in nude mice demyelinated lesion. We reproduced patients heterogeneity of remyelination in this model demonstrating that lymphocyte of some MS patient lymphocytes impede remyelination (El Behi , Sanson et al, 2017). We also noted that the remyelination-modulating effects of patient lymphocytes are mediated through the activation of macrophages.
2.  Macrophage role has primarily been described in terms of animal models and estimations based on post-mortem tissue. By studying macrophages derived from patient monocytes, we strive to elucidate how their innate properties and response to activating stimuli relate to the disease, both on a group level and individual patient level. Our findings reveal that MS patient macrophages present functional and molecular dysfunctionalities prior to any lesion exposure. Notably, MS patient monocytes exhibit a preferential differentiation toward CD16+ pro-inflammatory macrophages, an over exaggerated inflammatory response even in the absence of pro-inflammatory stimuli and a blockade of mitochondrial metabolism. All these features represents traits that are reminiscent of trained immunity (Fransson et al, submitted 2021).
3. We propose to complete these observations and to define precisely the molecular mechanism leading to MS patient macrophage overactivation by studying epigenetic regulation (histone modification, regulation of long non coding RNA) of MS patient macrophages.
4.  We also developed a method to identify key regulators in networks of several altered genes. This was done according to a pre-defined network of gene interactions. Testing a pro-inflammatory network for the possibility to control genes that are dysregulated in MS, we identified biologically and pathologically relevant genes as key drivers, supporting the framework of the method (Bassignana et al, Network neuroscience in review https://arxiv.org/abs/2003.08913).

Our preliminary results evidence that macrophages contribute to an inflammatory environment, and that patient heterogeneity in both lymphocytes and macrophages impact this contribution. Further research using these and similar models could be useful for both developing new treatments and predicting effects for each patient.