Search

Microglia, resident myeloid immune cells of the central nervous system (CNS), actively shape the circuitry of the brain, maintain CNS homeostasis during the steady state and orchestrate immune responses upon CNS injury. Both canonical and non-canonical functions of the macroautophagy/autophagy-related protein ATG5 regulate myeloid cell survival and immune responses. Here, we report that loss of ATG5 in postnatal microglia does not perturb CNS tissue integrity, microglial cell survival, or immune activation. Learning task performances were unchanged in mutant mice. Furthermore, lack of ATG5 expression in microglia had no impact on the development of experimental autoimmune encephalomyelitis. These data indicate that, basal autophagy, identified to be essential for the survival and function of neuronal cells, is not required to maintain CNS homeostasis if absent in adult microglia and ATG5 expression is dispensable for the development of autoimmune neuroinflammation. Abbreviations Ag, antigen; APC, antigen presenting cell; ATG/ Atg , autophagy-related; CD, cluster of differentiation; CNS, central nervous system; DC, dendritic cell; EAE, experimental autoimmune encephalomyelitis; fl, floxed; LAP, LC3-associated phagocytosis; LC3, microtubule-associated protein 1 light chain 3; MFI, median fluorescence intensity; MHCII, major histocompatibility complex class II; MOG, myelin oligodendrocyte glycoprotein; MS, multiple sclerosis.

Whereas central nervous system (CNS) homeostasis is highly dependent on tissue surveillance by immune cells, dysregulated entry of leukocytes during autoimmune neuroinflammation causes severe immunopathology and neurological deficits. To invade the CNS parenchyma, encephalitogenic T helper (T H ) cells must encounter their cognate antigen(s) presented by local major histocompatibility complex (MHC) class II-expressing antigen-presenting cells (APCs). The precise mechanisms by which CNS-associated APCs facilitate autoimmune T cell reactivation remain largely unknown. We previously showed that mice with conditional deletion of the gene encoding the essential autophagy protein ATG5 in dendritic cells (DCs) are resistant to EAE development. Here, we report that the nicotinamide adenine dinucleotide phosphate (NADPH) oxidase 2, also known as CYBB/NOX2, in conventional DCs (cDCs) regulates endocytosed MOG (myelin oligodendrocyte protein) antigen processing and supports MOG-antigen presentation to CD4 + T cells through LC3-associated phagocytosis (LAP). Genetic ablation of Cybb in cDCs is sufficient to restrain encephalitogenic T H cell recruitment into the CNS and to ameliorate clinical disease development upon the adoptive transfer of MOG-specific CD4 + T cells. These data indicate that CYBB-regulated MOG-antigen processing and LAP in cDCs licenses encephalitogenic T H cells to initiate and sustain autoimmune neuroinflammation. Abbreviations : Ag: antigen; APC: antigen-presenting cell; AT: adoptive transfer; ATG/ Atg : autophagy-related; BAMs: border-associated macrophages; BMDC: bone marrow-derived DC; CD: cluster of differentiation; CNS: central nervous system; CSF2/GM-CSF: colony stimulating factor 2 (granulocyte-macrophage); CYBB/NOX2/gp91 phox : cytochrome b-245, beta polypeptide; DC: dendritic cell; EAE: experimental autoimmune encephalomyelitis; fl: floxed; FOXP3: forkhead box P3; GFP: green fluorescent protein; H2-Ab: histocompatibility 2, class II antigen A, beta 1; IFN: interferon; IL: interleukin; ITGAX/CD11c: integrin subunit alpha X; LAP: LC3-associated phagocytosis; MAP1LC3/LC3: microtubule associated protein 1 light chain 3; MFI: median fluorescence intensity; MG: microglia; MHCII: major histocompatibility complex class II; MOG: myelin oligodendrocyte glycoprotein; MS: multiple sclerosis; NADPH: nicotinamide adenine dinucleotide phosphate; ODC: oligodendroglial cell; OVA: ovalbumin; pDC: plasmacytoid DC; Ptd-L-Ser: phosphatidylserine; PTPRC: protein tyrosine phosphatase, receptor type, C; ROS: reactive oxygen species; SLE: systemic lupus erythematosus; T H cells: T helper cells; TLR: toll-like receptor; ZBTB46: zinc finger and BTB domain containing 46.

Although it is known for long time that the peripheral nervous system has the capacity for self-regeneration, the molecular mechanisms by which Schwann cells and extracellular matrix (ECM) guide the injured axons to regrow along their original path, remains a poorly understood process. Due to the importance of ECM molecules during development, constitutive mutant organisms display increased lethality, therefore, conditional or inducible strategies have been used to increase the survival of the organisms and allow the study of the role of ECM proteins. In a recent report published in Neuron, Isaacman-Beck and colleagues (2015) used these pioneering genetic studies on zebrafish combined with in vivo fluorescent imaging, to investigate the micro-environmental conditions required for targeted regeneration of the dorsal motor nerve of zebrafish larvae after laser-transection. A candidate gene approach targeting lh3 basal laminar collagen substrates revealed that the lh3 substrate col4α5 regulates dorsal nerve regeneration by destabilizing misdirected axons. Col4α5 was upregulated in a small population of lh3 expressing Schwann cells located ventrally and ventro-laterally to the injury site and found to co-localize with the molecule slit guidance ligand 1 (slit1a). Capitalizing on the crucial observations of mistargeted regeneration of dorsal nerves in mutant larvae, they put forward a model in which Schwann cells shape an environment that allows and directs axonal regeneration to their original synaptic target. In the light of Isaacman-Beck and colleagues (2015) findings, we will review how their study contributes to the research field, and comment on its potential implications for promoting nerve regeneration after injury.