Neutrofielen: ondergewaardeerde spelers in de pathogenese van multiple sclerose

Multiple sclerosis (MS) is the most common immune-mediated disease of the central nervous system (CNS), affecting about 2.8 million people worldwide, of which 13.000 in Belgium. Unfortunately, no curing treatment is available, leaving these patients with a treatment strategy to reduce symptoms and slow down neurodegeneration, which is far from ideal. Despite decades of research, the exact pathogenesis and cause of this disease is not fully understood, leaving a multitude of unanswered questions. With the adaptive immune system always thought to be most important for driving MS disease course, the innate immune system is left seriously understudied. Belonging to this innate arm are neutrophils, the first-responding cells to fight infection or inflammation in the body, and the most numerous circulating leukocytes. With their short lifespan, they are challenging to study in a laboratory environment and in situ. Hence, this cell type is often overlooked in chronic inflammatory or autoimmune conditions, such as MS. However, in animal models of MS, a significant body of evidence was already gathered, supporting the importance of neutrophils in the early phases of disease. Therefore, the aim of this PhD project was to elucidate the involvement of neutrophils in the pathogenesis of MS. We explored the involvement of neutrophils in the broader context of MS through various approaches. Our findings revealed that circulating neutrophils from MS patients exhibit increased expression of CD62L compared to those from healthy donors. Additionally, single-cell RNA sequencing identified multiple distinct neutrophil subsets within the circulation, each characterized by unique transcriptional signatures. Notably, we observed differential expression of interesting genes such as ANXA1, IFITM3 and S100P, in neutrophils from untreated RRMS patients compared to those from natalizumab-treated patients or healthy donors. Furthermore, we demonstrated that BTK inhibitors, an upcoming group of therapy for autoimmune diseases, interfere with neutrophil's fundamental effector functions in vitro. This finding may have important implications for patients receiving BTK inhibitors, particularly regarding their immune response to infections. Moreover, this research suggests a novel mechanism of action for BTK inhibitors in autoimmune diseases, as they may attenuate activated neutrophils in pro-inflammatory environments. Lastly, we explored the possible involvement of neutrophils in one of the main hallmarks of MS pathology: demyelination. We discovered that human neutrophils take up myelin (debris) via complement-dependent pathways, specifically through the C3/CR3 pathway. Prolonged exposure to myelin debris induced a dose-dependent pro-inflammatory phenotype in neutrophils, characterized by an increased oxidative burst, NET release, chemokine production and inflammatory gene expression. Our research demonstrates that neutrophils are more than simple first-line defending cells; they may play a substantial role in various aspects of MS disease progression, potentially influencing disease outcomes and providing new targets for therapeutic intervention. Altogether, this PhD research highlighted the critical involvement of human neutrophils in various aspects of MS pathogenesis, offering valuable insights into their potential contribution to disease progression. This work lays a foundation for further investigations in patient samples or animal models, in an attempt to bridge knowledge gaps and contribute to the development of new therapeutic options for all MS patients.