Resolution of inflammation during multiple sclerosis

Abstract

Multiple sclerosis (MS) is a frequent autoimmune demyelinating disease of the central nervous system (CNS). There are three clinical forms described: relapsing-remitting multiple sclerosis (RRMS), the most common initial presentation (85%) among which, if not treated, about half will transform, into the secondary progressive multiple sclerosis (SPMS) and the primary progressive MS (PPMS) (15%) that is directly progressive without superimposed clinical relapses. Inflammation is present in all subsets of MS. The relapsing/remitting form could represent itself a particular interest for the study of inflammation resolution even though it remains incomplete in MS. Successful resolution of acute inflammation is a highly regulated process and dependent on mechanisms engaged early in the inflammatory response that are scarcely studied in MS. Moreover, recent classes of disease-modifying treatment (DMTs) that are effective against RRMS act by re-establishing the inflammatory imbalance, taking advantage of the pre-existing endogenous suppressor. In this review, we will discuss the active role of regulatory immune cells in inflammation resolution as well as the role of tissue and non-hematopoietic cells as contributors to inflammation resolution. Finally, we will explore how DMTs, more specifically induction therapies, impact the resolution of inflammation during MS.

Keywords: Astrocytes; Blood-brain-barrier; Induction therapies; Innate immune cells; Multiple sclerosis; Neurovascular unit; Suppressive immune cells.

Fig. 1

Suppressive immune cells involved in inflammation resolution. Foxp3⁺ Treg cells affect priming, proliferation, and polarization of effector T cells both in the CNS and the periphery. Tr1 cells produce the anti-inflammatory cytokine IL-10 and kill effector cells via granzyme-B and perforin. Qa-1-restricted CD8⁺ cells have a cytotoxic effect on activated CD4⁺ T cells. Bregs secrete IL-35 and TGF-β that suppress APC function. NK cell engagement of NCRs suppresses CD4⁺ T cell proliferation and exerts a cytotoxic activity via the release of granzyme-B, perforin, and of the immunosuppressive adenosine. CNS-derived MDSCs suppress proliferation and promote cell death of lymphocytes

Fig. 2

Schematic representation of the CNS at steady-state and during a relapse. a. Healthy CNS. The endothelial cells of the BBB are ensheeted by astrocytic end-feet. The BBB is impermeable notably to leukocytes. Oligodendrocytes form the myelin layer that surrounds the axon. b CNS during MS. The blood-brain barrier is disrupted and the endothelial permeability is increased. The astrocytic end-feet are detached, allowing leukocytes to transmigrate and trigger an inflammatory cascade. Inflammatory signals produced by leukocytes activate astrocytes. The myelin sheet is disrupted and phagocytes start to remove myelin debris. Neurons are further activated during the inflammatory reaction

Fig. 3

CNS network mechanism promoting resolution. BBB permeability restoration: Shh derived from astrocytes promotes Netrin 1 production by endothelial cells. This pathway reduces the BBB permeability and limits leukocyte infiltration. Astrocytes trap T-cells: activated astrocytes form a physical barrier that limits leucocyte infiltration. Astrocyte suppressive mechanisms: activated astrocytes produce anti-inflammatory cytokines that repress encephalitogenic T cells. Treg induction by neurons: neurons can repolarize encephalitogenic T cell into FoxA1⁺ Tregs. Foamy macrophage-suppressive mechanisms: foamy macrophages produce anti-inflammatory cytokine that contribute to inflammation resolution