Microglial autophagy–associated phagocytosis is essential for recovery from neuroinflammation

Abstract

Multiple sclerosis (MS) is a leading cause of incurable progressive disability in young adults caused by inflammation and neurodegeneration in the central nervous system (CNS). The capacity of microglia to clear tissue debris is essential for maintaining and restoring CNS homeostasis. This capacity diminishes with age, and age strongly associates with MS disease progression, although the underlying mechanisms are still largely elusive. Here, we demonstrate that the recovery from CNS inflammation in a murine model of MS is dependent on the ability of microglia to clear tissue debris. Microglia-specific deletion of the autophagy regulator Atg7, but not the canonical macroautophagy protein Ulk1, led to increased intracellular accumulation of phagocytosed myelin and progressive MS-like disease. This impairment correlated with a microglial phenotype previously associated with neurodegenerative pathologies. Moreover, Atg7-deficient microglia showed notable transcriptional and functional similarities to microglia from aged wild-type mice that were also unable to clear myelin and recover from disease. In contrast, induction of autophagy in aged mice using the disaccharide trehalose found in plants and fungi led to functional myelin clearance and disease remission. Our results demonstrate that a noncanonical form of autophagy in microglia is responsible for myelin degradation and clearance leading to recovery from MS-like disease and that boosting this process has a therapeutic potential for age-related neuroinflammatory conditions.

Fundamentally Different Roles of Neuronal TNF Receptors in CNS Pathology: TNFR1 and IKKβ Promote Microglial Responses and Tissue Injury in Demyelination, TNFR2 Protects in Excitotoxicity in Mice

“…Here we show that both neuronal TNFR1 and IKKβ accelerate microglia and astrocyte responses, demyelination and the onset of axon damage in the demyelination models, indicating common signaling pathways. Neuronal TNFR1 also induced the induction of autophagy in glial cells in the demyelinating lesions in the CPZ model, possibly in myelin-phagocytosing microglia, as recently described [46], and re ecting the increased demyelination and demand for clearance of myelin debris in control mice. Axonal damage and OLG loss were dependent upon the presence of neuronal TNFR1, not neuronal IKKβ during cuprizone demyelination, suggesting that other TNFR1 pathways signal axon and OLG pathology in this model.…”

“…Considering that both TNF signaling and oxidative stress are strong inducers of autophagy [44,45], and that autophagy in microglia is responsible for the degradation and clearance of myelin debris in vitro [46], we also investigated the effect of neuronal TNFR1 on autophagy in CPZ demyelination. We measured autophagy levels in the brain sections from naïve and CPZ-fed nTNFR1KO and control mice by immunostaining for LC3, a key component of autophagosomes.…”

Assessing Autophagy in Microglia: A Two-Step Model to Determine Autophagosome Formation, Degradation, and Net Turnover

“…In the brain, initial studies focused on its major role in neuronal survival (3,4), but more recent evidence suggests that autophagy also controls health and function of other brain cell types, including microglia, the brain macrophages (1,5). Autophagy controls several processes in microglia, including metabolic fitness (6), inflammation, phagocytosis of amyloid beta in rodent models of Alzheimer's disease (7), degradation of extracellular beta-amyloid fibrils (8) and synuclein (9), myelin phagocytosis in acute experimental encephalomyelitis (10), as well as synaptic pruning and social behavior in mice (11). Overall, autophagy is emerging as a major controller of immune cell function, regulating innate and adaptive immune responses (12).…”

Mitophagy Modulation, a New Player in the Race against ALS

“…In this context, a paradigmatic case was reported recently about microglia-selective deletion of ATG7 in a multiple sclerosis model: defective autophagy-related phagocytosis in microglia impairs myelin debris elimination. The accumulation of these remains of myelin leads to neuroinflammation and the inability to remyelinate neurons, due to the lack of ATG7 [109]. Curiously, trehalose is able to reverse the neurodegenerative phenotype in the aged mouse model because of its autophagy stimulation activity.…”