Microglial neurophagy regulated by UDP/P2Y6 and sialylation/galectin-3
Guy C. Brown, Koji Nomura, David Allendorf, Anna Vilalta and Stefan Milde
Department of Biochemistry, University of Cambridge, UK
Neurophagy is the phagocytosis of live neurons or neuronal parts by other cells, first described by Marinesco in the 1890's. P2Y6 is a UDP receptor on microglia required for microglial engulfment of neurons. We found that stressed neurons release UDP, which activated P2Y6 receptors on microglia, inducing microglial phagocytosis of live neurons. Blocking the P2Y6 receptor prevented inflammatory loss of neurons in culture and in vivo. We now report that P2Y6 ko mice lack neurophagy, and are protected against neuronal loss in vivo in models of i) stroke, ii) Parkinson's disease and iii) Alzheimer's disease.
The terminal sugar residue of glycoproteins and glycolipids is normally sialic acid, which inhibits phagocytosis via Siglec receptors. We found that activated microglia released a sialidase activity that desialylated microglia and neighbouring neurons. Activated microglia also released galectin-3, which bound desialylated (but not sialylated) neurons, opsonising such neurons for phagocytosis by microglia by also binding the phagocytic receptor MerTK. Blocking galectin-3, MerTK or sialidase prevented LPS-induced microglial phagocytosis of neurons. Knockout of MerTK prevented microglial phagocytosis of stressed neurons in culture and in a mouse model of stroke. Knockout of galectin-3 prevented neuronal loss in a mouse model of brain trauma. LPS induced desialylation of microglia apparently mediated by the sialidase Neu1. Desialylation of microglia increased phagocytosis and cytokine release, prevented by TLR4 inhibition. Desialylation may be an important regulator of microglial activation and microglial-neuronal interactions.
Vilalta A, Brown GC (2017) Neurophagy, the phagocytosis of live neurons and synapses by glia, contributes to brain development and disease. FEBS J. Nov 10.
Nomura K, Vilalta A, Allendorf DH, Hornik TC, Brown GC (2017) Activated Microglia Desialylate and Phagocytose Cells via Neuraminidase, Galectin-3, and Mer Tyrosine Kinase. J Immunol 198:4792-4801.
Yip PK et al (2017) Galectin-3 released in response to traumatic brain injury acts as an alarmin orchestrating brain immune response and promoting neurodegeneration. Sci Rep 7:41689.
Funding: Wellcome Trust and MRC.