The Role of Muscularis Macrophages in Mediating Local and Systemic Immune Responses in a Mouse Model of Multiple Sclerosis

Abstract

Multiple sclerosis (MS) is a chronic neurodegenerative disease, likely of autoimmune origin, which mainly affects the central nervous system (CNS). It is often associated with impaired gut motility, causing symptoms like constipation, diarrhea or faecal incontinence in most patients with MS. Recently, it was identified that the enteric nervous system (ENS), the intrinsic nervous system of the gastrointestinal tract, which regulates motility and secretion, is an additional autoimmune target in MS and its animal model, experimental autoimmune encephalomyelitis (EAE). <br/> Muscularis macrophages (MMs) are located in close proximity to enteric neurons. Both regulate each other by secreting survival factors that are essential for the function of the other population. MMs are known to be regulators of the local immune response in a variety of pathological conditions, such as post-operative ileus and intestinal infection with bacteria or helminths. Additionally, MM depletion was shown to impair gut motility. <br/> In this project, we investigated the involvement of MMs in the pathogenesis of EAE. To this end, we performed single-cell RNA sequencing and identified that MMs upregulate anti-inflammatory and neuron-associated genes. <br/> Furthermore, we established a model to combine EAE with MM depletion. <br/> We observed an exacerbated clinical outcome in MM-depleted mice that was associated with an earlier and increased infiltration of immune cells into the CNS, leading to a more severe axonal damage. <br/> Using high-dimensional flow cytometry, we identified that gut-associated effector T cells are activated earlier in MM-depleted animals due to an increase in the number of dendritic cells in the muscularis externa. Our results suggest an increased pathogenicity end encephalitogenicity of type 17 helper T cells that impair the blood brain barrier integrity and allow an early infiltration of immune cells into the CNS. <br/> Taken together, our study identifies MMs to be an essential regulator of the systemic immune response that originates in the gut and to display a novel target for potential MS therapies.