The Emerging Role of Neutrophil Granulocytes in Multiple Sclerosis

Abstract

Multiple sclerosis (MS) is a demyelinating disease of the central nervous system with a strong autoimmune, neurodegenerative, and neuroinflammatory component. Most of the common disease modifying treatments (DMTs) for MS modulate the immune response targeting disease associated T and B cells and while none directly target neutrophils, several DMTs do impact their abundance or function. The role of neutrophils in MS remains unknown and research is ongoing to better understand the phenotype, function, and contribution of neutrophils to both disease onset and stage of disease. Here we summarize the current state of knowledge of neutrophils and their function in MS, including in the rodent based MS model, and we discuss the potential effects of current treatments on these functions. We propose that neutrophils are likely to participate in MS pathogenesis and their abundance and function warrant monitoring in MS.

Deficiency of Socs3 leads to brain-targeted experimental autoimmune encephalomyelitis via enhanced neutrophil activation and ROS production

“…Neutrophils are critically involved in the pathophysiology of numerous CNS diseases, including MS, NMOSD, Alzheimer's disease, and cerebral ischemia (15,25,(87)(88)(89). The findings from our study may have relevance to NMOSD in addition to MS, given the well-documented presence of neutrophils in CNS lesions and cerebrospinal fluid and findings that neutrophils contribute to astrocyte dysfunction and inflammation in NMOSD animal models (25,26).…”

“…These differences may reflect the timing at which G-CSF signaling is interrupted. Collectively, these findings indicate that the biological functions of neutrophils in EAE are timing, context, and model dependent, with both beneficial and detrimental behaviors (11)(12)(13)15). Our RNA-Seq analysis identified numerous genes that are differentially expressed in Socs3-deficient neutrophils in response to G-CSF, compared with Socs3 fl/fl mice.…”

“…Neutrophils initiate immune responses by secretion of proinflammatory cytokines/chemokines, degranulation, generation of ROS, formation of neutrophil extracellular traps (NETs), and antigen presentation (6,(8)(9)(10). Neutrophils are involved in the pathology of CNS autoimmune diseases, such as MS/EAE and neuromyelitis optica spectrum disorder (NMOSD) (11)(12)(13)(14)(15). Neutrophils contribute to EAE disease by secretion of proinflammatory cytokines (16,17), promoting maturation of antigen-presenting cells, such as dendritic cells and macrophages (18), and disruption of the blood-spinal cord barrier (19).…”

The Brain Entangled: The Contribution of Neutrophil Extracellular Traps to the Diseases of the Central Nervous System

“…Strikingly, the increased plasma levels of NE in MS patients are associated with clinical disability and lesion burden [57]. All aforementioned premises constitute a solid background for the proposed contribution of NET release to MS pathogenesis, but the functional link between these two phenomena is still far from being elucidated [58]. Accordingly, current studies focus on an in-depth analysis of the role of NETs and their constituents in MS-related inflammation [58,59].…”

From immunohistological to anatomical alterations of human pancreas in type 1 diabetes: New concepts on the stage

“…A strong trigger to the initial evaluation of neutrophils in T1D derives from the fact that such cells are more active immunological mediators than previously thought. Indeed, their role has been found critical in multiple human autoimmune diseases (eg, lupus erythematous, vasculitis, and rheumatoid arthritis [RA]) and causally associated to the onset of such diseases in several animal models . In animal models of T1D, neutrophils recruitment in pancreas during autoimmune diabetes progression has been shown to be essential in disease onset and severity .…”