Microglial Phagocytosis—Rational but Challenging Therapeutic Target in Multiple Sclerosis

Abstract

Multiple sclerosis (MS) is the most common autoimmune and demyelinating disease of the central nervous system (CNS), characterized, in the majority of cases, by initial relapses that later evolve into progressive neurodegeneration, severely impacting patients’ motor and cognitive functions. Despite the availability of immunomodulatory therapies effective to reduce relapse rate and slow disease progression, they all failed to restore CNS myelin that is necessary for MS full recovery. Microglia are the primary inflammatory cells present in MS lesions, therefore strongly contributing to demyelination and lesion extension. Thus, many microglial-based therapeutic strategies have been focused on the suppression of microglial pro-inflammatory phenotype and neurodegenerative state to reduce disease severity. On the other hand, the contribution of myelin phagocytosis advocating the neuroprotective role of microglia in MS has been less explored. Indeed, despite the presence of functional oligodendrocyte precursor cells (OPCs), within lesioned areas, MS plaques fail to remyelinate as a result of the over-accumulation of myelin-toxic debris that must be cleared away by microglia. Dysregulation of this process has been associated with the impaired neuronal recovery and deficient remyelination. In line with this, here we provide a comprehensive review of microglial myelin phagocytosis and its involvement in MS development and repair. Alongside, we discuss the potential of phagocytic-mediated therapeutic approaches and encourage their modulation as a novel and rational approach to ameliorate MS-associated pathology.

Microglial Pruning: Relevance for Synaptic Dysfunction in Multiple Sclerosis and Related Experimental Models

“…The role of the complement in MS pathology is well established, as reviewed by Ingram et al, and it has also been proposed as a biomarker of the disease [ 124 ]. Alongside its known role in the opsonization of myelin fragments [ 124 , 125 , 126 ] and in the progression of the disease [ 49 , 127 , 128 ], much evidence also suggests its contribution to MS- and EAE-related synaptopathy. In MS, elevated levels of C3 in CSF correlate both with those of the light subunit of the neurofilament protein, marker of ongoing neuronal damage, and with levels of clinical disability [ 129 ].…”

“…At the neuropathologic level, while activation of the complement system has been extensively reported in WM demyelinating lesions [ 125 , 134 , 135 , 136 ], its role in GM damage is unclear. Low levels of complement deposition were initially observed in purely cortical lesions, together with reduced immunoreactivity for C3d and C4d in combined GM and WM lesions, while enhanced expression of elements of the membrane attack complex (MAC) (C1q, C3d and C5b-9) were found in WM demyelinating lesions [ 137 ].…”

Microglial Cell Morphology and Phagocytic Activity Are Critically Regulated by the Neurosteroid Allopregnanolone: A Possible Role in Neuroprotection

“…Indeed, an in vivo model of neuroinflammation in which the BBB is maintained, like peripheral LPS injection, did not demonstrate enhanced phagocytosis [ 45 ]. In contrast, debris uptake by microglia has been documented in neuropathologies, where BBB is compromised, such as stroke or multiple sclerosis [ 46 , 47 ]. Phagocytosis is now recognized as a critical mechanism for neuroprotection and regeneration that is regulated by serum factors.…”

Myelin Repair: From Animal Models to Humans

“…Finally, aging also affects microglial cells and macrophages, which play a crucial role in remyelination, by removing myelin debris that inhibits remyelination (for a review, see Pinto and Fernandes, 2020). Aged microglial cells become dystrophic, and their processes become less motile (Wong, 2013;Hefendehl et al, 2014;Rawji et al, 2018).…”

“…Improving myelin clearance is a major challenge. No drug is currently available for specifically preventing the aging-induced decrease in microglial phagocytosis, although several candidate molecules have been identified (Pinto and Fernandes, 2020). These molecules include two polyunsaturated fatty acids (DHA and EPA) (Chen et al, 2014), the endocannabinoid 2-AG (Mecha et al, 2019), and an experimental recombinant human antibody rhIGM22 (Zorina et al, 2018).…”