Neuroprotective Potential of Dendritic Cells and Sirtuins in Multiple Sclerosis

Abstract

Myeloid cells, including parenchymal microglia, perivascular and meningeal macrophages, and dendritic cells (DCs), are present in the central nervous system (CNS) and establish an intricate relationship with other cells, playing a crucial role both in health and in neurological diseases. In this context, DCs are critical to orchestrating the immune response linking the innate and adaptive immune systems. Under steady-state conditions, DCs patrol the CNS, sampling their local environment and acting as sentinels. During neuroinflammation, the resulting activation of DCs is a critical step that drives the inflammatory response or the resolution of inflammation with the participation of different cell types of the immune system (macrophages, mast cells, T and B lymphocytes), resident cells of the CNS and soluble factors. Although the importance of DCs is clearly recognized, their exact function in CNS disease is still debated. In this review, we will discuss modern concepts of DC biology in steady-state and during autoimmune neuroinflammation. Here, we will also address some key aspects involving DCs in CNS patrolling, highlighting the neuroprotective nature of DCs and emphasizing their therapeutic potential for the treatment of neurological conditions. Recently, inhibition of the NAD+-dependent deac(et)ylase sirtuin 6 was demonstrated to delay the onset of experimental autoimmune encephalomyelitis, by dampening DC trafficking towards inflamed LNs. Thus, a special focus will be dedicated to sirtuins’ role in DCs functions.

Investigating shared genetic architecture between obesity and multiple sclerosis

“…B cell depletion may reduce the proinflammatory cytokines produced by B cells, CD4+ and CD8 + T cells which can effectively reduce MS relapses 86,87 . NK and DC cells control T cell activation in CNS autoimmunity, and reduced the risk of MS 88,89 . Mast cells participate in the pathogenesis of MS by promoting angiogenesis 90 .…”

Immune Regulatory Functions of Macrophages and Microglia in Central Nervous System Diseases

“…As reviewed by Piacente et al, sirtuin 1 (SIRT1) and sirtuin 2 (SIRT2), which are NAD + -dependent deacetylases, possibly play a role in regulating neuroinflammation and microglial activation in MS [ 153 ]. Studies of SIRT2 using LPS-induced neuroinflammation have yielded conflicting results, with one group demonstrating SIRT2 −/− mice experiencing an increase in pro-inflammatory cytokines and morphological changes in microglia, while another group found that administration of an SIRT2 inhibitor significantly reduced microglial activation, as well as TNF-α and IL-6 expression [ 153 , 154 , 155 ]. Current research on SIRT1 is more cohesive, however, with several groups reporting that SIRT1 may promote the transformation of activated microglia from a pro-inflammatory M1-like phenotype to a neuroprotective M2-like phenotype in EAE mice [ 153 , 156 , 157 ].…”

“…Studies of SIRT2 using LPS-induced neuroinflammation have yielded conflicting results, with one group demonstrating SIRT2 −/− mice experiencing an increase in pro-inflammatory cytokines and morphological changes in microglia, while another group found that administration of an SIRT2 inhibitor significantly reduced microglial activation, as well as TNF-α and IL-6 expression [ 153 , 154 , 155 ]. Current research on SIRT1 is more cohesive, however, with several groups reporting that SIRT1 may promote the transformation of activated microglia from a pro-inflammatory M1-like phenotype to a neuroprotective M2-like phenotype in EAE mice [ 153 , 156 , 157 ]. Additionally, SIRT1 may play a role in regulating inflammation, as upregulation of SIRT1 in LPS-treated microglial cell line has been shown to attenuate the expression of IL-1β and IL-6 [ 153 , 158 ].…”

Role of Sirtuins in Physiology and Diseases of the Central Nervous System

“…SIRTs deserve attention regarding MS pathology as relevant regulators of the main processes involved in the background of the disease: (auto)immune response, neurodegeneration, and metabolic pathway [ 126 ]. The activity of SIRTs was extensively investigated in experimental autoimmune encephalomyelitis (EAE), which is a widely used animal model of MS, and more recently also in clinical studies involving MS subjects.…”

“…Inhibition of SIRT6 delayed EAE onset by early downregulation of CD40 expression on DCs and T cells infiltration in the CNS. In studies on MS subjects in the earliest phase of disease, presenting with high levels of DCs in peripheral blood, SIRT6 inhibition was demonstrated to interfere with DCs migration and delay conversion from clinically isolated syndrome (first clinical manifestation) to the relapsing-remitting stage of disease [ 126 ]. The role of SIRT7 in MS has been less recognized.…”