Looking to the Future of the Role of Macrophages and Extracellular Vesicles in Neuroinflammation in ALS

Abstract

Neuroinflammation is a common pathological feature of amyotrophic lateral sclerosis (ALS). Although scientific evidence to date does not allow defining neuroinflammation as an ALS trigger, its role in exacerbating motor neuron (MNs) degeneration and disease progression is attracting research interest. Activated CNS (Central Nervous System) glial cells, proinflammatory peripheral and infiltrated T lymphocytes and monocytes/macrophages, as well as the immunoreactive molecules they release, represent the active players for the role of immune dysregulation enhancing neuroinflammation. The crosstalk between the peripheral and CNS immune cells significantly correlates with the survival of ALS patients since the modification of peripheral macrophages can downregulate inflammation at the periphery along the nerves and in the CNS. As putative vehicles for misfolded protein and inflammatory mediators between cells, extracellular vesicles (EVs) have also drawn particular attention in the field of ALS. Both CNS and peripheral immune cells release EVs, which are able to modulate the behavior of neighboring recipient cells; unfortunately, the mechanisms involved in EVs-mediated communication in neuroinflammation remain unclear. This review aims to synthesize the current literature regarding EV-mediated cell-to-cell communication in the brain under ALS, with a particular point of view on the role of peripheral macrophages in responding to inflammation to understand the biological process and exploit it for ALS management.

Neuroinflammation and Neurodegenerative Diseases: How Much Do We Still Not Know?

“…Accordingly, changes in number or functional quality of peripheral macrophages can modulate inflammation at the periphery along nerves and in the CNS [18][19][20][21]. Extracellular vehicles (EVs) from misfolded proteins and mediators of inflammation released by the cells appear to have a fundamental function in the inflammatory amplification [6], as recently reported by the literature.…”

“…Neuroinflammation is evoked by typical immune cells residing in the brain and well known to have a key role in central nervous system (CNS) homeostasis and the development of neurodegenerative diseases (NDs), constituting their typical hallmark [3][4][5]. However, recent evidence suggests that both peripheral and infiltrating monocytes, as well as cells of clonotypic immunity, constitute other crucial actors of neuroinflammation [5,6]. Nevertheless, such evidence needs to be supported by larger studies, even if the growing data obtained in recent years appear promising and demonstrate the crucial contribution of this immune component in brain health and disease [3][4][5][6].…”

“…However, recent evidence suggests that both peripheral and infiltrating monocytes, as well as cells of clonotypic immunity, constitute other crucial actors of neuroinflammation [5,6]. Nevertheless, such evidence needs to be supported by larger studies, even if the growing data obtained in recent years appear promising and demonstrate the crucial contribution of this immune component in brain health and disease [3][4][5][6].…”

A Potential Role of Interleukin-5 in the Pathogenesis and Progression of Amyotrophic Lateral Sclerosis: A New Molecular Perspective

“…Both types of immune cells release cytokines with either anti-inflammatory or pro-inflammatory properties, thereby influencing the resolution or exacerbation of neuroinflammation based on their functional roles and responses. Nevertheless, the precise temporal sequence and causal relationship between neuronal degeneration and neuroinflammation remain incompletely elucidated [37,38].…”

Recent Research Trends in Neuroinflammatory and Neurodegenerative Disorders

“…Recently, immune dysregulation has been suspected [ 171 , 172 , 173 ], with neuroinflammation being invoked in general [ 174 , 175 , 176 ] and for ALS in particular [ 177 , 178 , 179 ], especially concerning activation of microglia and astrocytes [ 180 , 181 ]. It is interesting that microglia communicate with [ 182 ], and can be activated by [ 183 ], mast cells, unique effector immune cells that are ubiquitous in the body and are critical in allergies [ 184 ], but also inflammatory processes [ 185 ].…”