Molecular Mechanisms of Immunosenescene and Inflammaging: Relevance to the Immunopathogenesis and Treatment of Multiple Sclerosis

Abstract

Aging is characterized, amongst other features, by a complex process of cellular senescence involving both innate and adaptive immunity, called immunosenescence and associated to inflammaging, a low-grade chronic inflammation. Both processes fuel each other and partially explain increasing incidence of cancers, infections, age-related autoimmunity, and vascular disease as well as a reduced response to vaccination. Multiple sclerosis (MS) is a lifelong disease, for which considerable progress in disease-modifying therapies (DMTs) and management has improved long-term survival. However, disability progression, increasing with age and disease duration, remains. Neurologists are now involved in caring for elderly MS patients, with increasing comorbidities. Aging of the immune system therefore has relevant implications for MS pathogenesis, response to DMTs and the risks mediated by these treatments. We propose to review current evidence regarding markers and molecular mechanisms of immunosenescence and their relevance to understanding MS pathogenesis. We will focus on age-related changes in the innate and adaptive immune system in MS and other auto-immune diseases, such as systemic lupus erythematosus and rheumatoid arthritis. The consequences of these immune changes on MS pathology, in interaction with the intrinsic aging process of central nervous system resident cells will be discussed. Finally, the impact of immunosenescence on disease evolution and on the safety and efficacy of current DMTs will be presented.

Keywords: T/B cells; astrocytes; disease modifying therapies; immunosenescence; inflammaging; microglia; multiple sclerosis; oligodendrocytes.

Figure 1

Pathophysiology of multiple sclerosis. (A) In the early inflammatory phase of MS, peripheral adaptive immune cells infiltrate the CNS through a disrupted BBB. These activated cells interact with each other and the resident cells of the CNS. They secrete cytokines (e.g., IFNg by Th1, IL6/17 by Th17, GM-CSF, IL6, TNFa by B cells) and cytotoxic molecules (e.g., granzyme B by CD8⁺ T cells). B cells can further evolve into autoantibody-producing plasma cells. As a consequence, T and B cells activate macrophages and microglia, which produce cytokines, nitric oxide, and ROS. This cytotoxic pro-inflammatory environment breaks down the myelin sheaths around axons and induces energy failure in the axon. Macrophages and microglia can still clear the myelin debris, allowing for the recruitment of OPCs that will partially remyelinate the lesion. (B) In the progressive phase of MS, T and B cell infiltrates are reduced. Remarkably, plasmablasts and plasma B cells form tertiary follicle-like structures in the meninges. The BBB is closed and the inflammation is sustained by innate CNS-resident cells, i.e., microglia and astrocytes. They produce cytokines (TNFa, IL6) and release ROS, causing myelin damage. Although microglia are primed into a pro-inflammatory phenotype, their phagocytic capacities are reduced. These features also characterize the senescence-associated phenotype of microglia and astrocytes. Myelin debris are improperly cleared, OPCs are less recruited and fail to differentiate. TNFa-mediated glutamate release from astrocytes results in excitotoxicity causing axonal damage. The ferrous iron released from the myelin, where it accumulates with age, is oxidized, which produces ROS, and incorporated by microglia, forming a phenotypical rim around the demyelinating lesions, both in the white and gray matter. These successive events are self-sustained and enhanced by senescent processes, resulting in a major oxidative burst, causing mitochondrial dysfunction, mitochondrial DNA damage, energy failure and axonal loss. BBB, blood brain barrier; B, B cell; CNS, central nervous system; GM-CSF, granulocyte-macrophage colony-stimulating factor; IFN, interferon; IL, interleukin; MS, multiple sclerosis; OPC, oligodendrocyte progenitor cell; ROS, reactive oxygen species; T, T cell; Th, T helper cell; TNF, tumor necrosis factor. Created with BioRender.com.

Figure 2

immunosenescence features in multiple sclerosis. Features of immunosenescence have been described in MS. The thymic involution (measurable by reduced TREC levels) induces the homeostatic proliferation of T cells. However, naïve T cells rapidly differentiate into memory T cells due to antigenic stimulation. While Th17 cells, and to a lesser extent, Tregs are expanded in the periphery, the latter fail to suppress Th17 cells. A subset of CD4⁺ T cells has lost the costimulatory signal CD28, marking the T cell exhaustion mainly through sustained CMV stimulation. These cells express the CX3CR1 receptor, favoring their migration through the BBB, as their ligand, fractalkine, has been found overexpressed in the cerebrospinal fluid (CSF). The B cell compartment is characterized by a reduction in immunoregulatory transitional B cells, but an increase in double negative B cells (DNBs) and ABCs. These three subsets (CD4⁺CD28⁻ T cells, DNBs, ABCs) have been linked to immunosenescence and detected in the CNS of MS patients. CD4⁺CD28⁻ T cells and double negative B cells produce TNFa, and granzyme B. CD4⁺CD28⁻ T cells produce also IL6, and double negative B cells produce LTa, hence corresponding to the senescence-associated secretory phenotype of these cells. ABCs produce TNFa and autoantibodies and polarize Th17 cells. In the CNS, both microglia and macrophages have impaired phagocytic properties, but while microglia are primed, macrophages lose their inflammatory reactiveness. Microglia further produce ROS and incorporate iron. Astrocytes produce also proinflammatory cytokines and ROS and release glutamate, inducing excitotoxicity. The oxidative burst causes mitochondrial dysfunction, and (mitochondrial) DNA damage. Autophagy is increased but impaired, which might induce the inflammasome. Moreover, telomeres shorten with age and disease progression. Interestingly, hypermethylation is a common feature in PBMCs from MS patients, found in several subsets as well as in brain tissues, while hypomethylation has on the contrary been linked to aging. Finally, miR-146a-5p and miR-155-5p are two major immuno-microRNAs with opposite effects on the integrity of the BBB, T cell migration and the differentiation of Th17 cells. Herein, miR-155-5p displays pro-inflammatory characteristics, but also supports the differentiation of Tregs. Four miRNAs (miR-20a/25/29c/149*) have been linked to brain atrophy. CMV, cytomegalovirus; CNS, central nervous system; CX3CR1, C-X3-C Motif Chemokine Receptor 1; B, B cell; ABC, age-associated B cell; DNB, double negative B cell; IL, interleukin; LTa, lymphotoxin A; Me, methylation; mt, mitochondrial; MS, multiple sclerosis; PBMCs, peripheral blood mononuclear cells; SASP, senescence-associated secretory phenotype; T, T cell; Th, T helper cell; TRECs, T cell receptor excision circles; Treg, regulatory T cell; TNF, tumor necrosis factor. Created with BioRender.com.