, Results are normalized to Gapdh, and are shown as ratios to the nonoperated (naive) value of WT mice. Values show the mean 6 S.E.M. *p < .05, **p < .005; unpaired Student's t-test. (b-j) Expression of SiglecH protein in the ipsilateral dorsal horn 3 days after L4 nerve injury. Immunoreactivity for Siglec-H (b,e,h, green) and Iba1 (c,f,i, red), and the merged images (d,g,j) of WT (b-g) and Siglech dtr/dtr (h-j) mice are shown, FIG URE 7 Siglec-H suppresses pro-inflammatory responses of microglia in a mouse neuropathic pain model. (a)
, Scale bar: 200 mm (b-d), 10 mm (e-j). (k) Expression of mRNA encoding proinflammatory cytokines (TNF-a and IL-1b) but not anti-inflammatory cytokines (IL-10 and TGF-b1) was upregulated in the ipsilateral dorsal horn of Siglech dtr/dtr mice. Ipsilateral L4 dorsal horn was obtained from WT and Siglech dtr/dtr mice at each time point after L4 nerve transection (n 5 3 for each time point), and mRNA expression was analyzed by qPCR. Results are normalized to Gapdh, and are shown as ratios to the nonoperated (naive) value of WT mice. Values show the mean 6 S.E.M. *p < .05, **p < 5.0 3 10 24 ; unpaired Student's t-test. (l-n) Microglial numbers in lamina I/IIo were unchanged between WT and Siglech dtr/dtr mice 7 days after injury. Merged images of Iba1 (green) and PKCg (red) immunostaining of WT (l) and Siglech dtr/dtr (m) mice are shown. The lamina I/IIo is surrounded by dotted lines. Scale bar: 200 mm. Microglial numbers in lamina I/IIo of contralateral (contra) and ipsilateral (ipsi) L4 dorsal horn were counted at 7d (n) (n 5 4; four images per animal). (o,p) Nerve injury-induced mechanical allodynia is exacerbated in Siglech dtr/dtr mice. The PWT of the contralateral (o) and ipsilateral (p) side was measured in WT and, Siglec-H expression in microglia. Note that faint signals for Siglec-H are predominantly observed in the endoplasmic reticulum/Golgi apparatus of microglia in Siglech dtr/dtr mice (arrows in h-j, high mag.)
Infiltrating monocytes trigger EAE progression, but do not contribute to the resident microglia pool, Nature Neuroscience, vol.14, pp.1142-1149, 2011. ,
P2Y(12) receptor on the verge of a neuroinflammatory breakdown, Mediators of Inflammation, p.975849, 2014. ,
Abnormal morphology of myelin and axon pathology in murine models of multiple sclerosis, Neurochemistry International, vol.81, pp.16-27, 2015. ,
Identification of genes preferentially expressed by microglia and upregulated during cuprizone-induced inflammation, Glia, vol.55, pp.777-789, 2007. ,
New tools for studying microglia in the mouse and human CNS, vol.113, pp.1738-1746, 2016. ,
The role of non-resident cells in Wallerian degeneration, Journal of Neurocytology, vol.13, pp.767-796, 1984. ,
, , 2006.
, Siglec-H is an IPC-specific receptor that modulates type I IFN secretion through DAP12, Blood, vol.107, pp.2474-2476
Sampling and signaling in plasmacytoid dendritic cells: the potential roles of Siglec-H, Trends in Immunology, vol.27, pp.255-260, 2006. ,
Onset and progression in inherited ALS determined by motor neurons and microglia, Science, vol.312, pp.1389-1392, 2006. ,
A DAP12-mediated pathway regulates expression of CC chemokine receptor 7 and maturation of human dendritic cells, Journal of Experimental Medicine, vol.194, pp.1111-1122, 2001. ,
,
Identification of a unique TGFbeta-dependent molecular and functional signature in microglia, Nature Neuroscience, vol.17, pp.131-143, 2014. ,
Sall1 is a transcriptional regulator defining microglia identity and function, Nature Immunology, vol.17, pp.1397-1406, 2016. ,
Role of macrophages in Wallerian degeneration and axonal regeneration after peripheral nerve injury, Acta Neuropathologica, vol.130, pp.605-618, 2015. ,
A neurodegeneration-specific gene-expression signature of acutely isolated microglia from an amyotrophic lateral sclerosis mouse model, Cell Reports, vol.4, pp.385-401, 2013. ,
Microglial CD33-related Siglec-E inhibits neurotoxicity by preventing the phagocytosis-associated oxidative burst, Journal of Neuroscience, vol.33, pp.18270-18276, 2013. ,
Mannose receptor expression specifically reveals perivascular macrophages in normal, injured, and diseased mouse brain, Glia, vol.49, pp.375-384, 2005. ,
G-protein-coupled receptor screen reveals a role for chemokine receptor CCR5 in suppressing microglial neurotoxicity, Journal of Neuroscience, vol.28, pp.11980-11988, 2008. ,
,
Gene-expression profiles and transcriptional regulatory pathways that underlie the identity and diversity of mouse tissue macrophages, Nature Immunology, vol.13, pp.1118-1128, 2012. ,
,
Fate mapping analysis reveals that adult microglia derive from primitive macrophages, Science, vol.330, pp.841-845, 2010. ,
Neural-immune interface in the rat area postrema, Neuroscience, vol.140, pp.1415-1434, 2006. ,
Origin, fate and dynamics of macrophages at central nervous system interfaces, Nature Immunology, vol.17, pp.797-805, 2016. ,
A new type of microglia gene targeting shows TAK1 to be pivotal in CNS autoimmune inflammation, Nature Neuroscience, vol.16, pp.1618-1626, 2013. ,
Tissue-resident macrophages originate from yolk-sac-derived erythro-myeloid progenitors, Nature, vol.518, pp.547-551, 2015. ,
Microglia Versus Myeloid Cell Nomenclature during Brain Inflammation, Frontiers in Immunology, vol.6, p.249, 2015. ,
, TREM2 variants in Alzheimer's disease, vol.368, pp.117-127, 2013.
Sall1 regulates cortical neurogenesis and laminar fate specification in mice: implications for neural abnormalities in TownesBrocks syndrome, Disease Models & Mechanisms, vol.5, pp.351-365, 2012. ,
The P2Y12 receptor regulates microglial activation by extracellular nucleotides, Nature Neuroscience, vol.9, pp.1512-1519, 2006. ,
The microglial sensome revealed by direct RNA sequencing, Nature Neuroscience, vol.16, pp.1896-1905, 2013. ,
Visualization of microglia in living tissues using Iba1-EGFP transgenic mice, Journal of Neuroscience Research, vol.81, pp.357-362, 2005. ,
Ginhoux, F. (2015). C-Myb(1) erythro-myeloid progenitor-derived fetal monocytes give rise to adult tissue-resident macrophages, Immunity, vol.42, pp.665-678 ,
Microglia-specific localisation of a novel calcium binding protein, Iba1, Brain Research Molecular Brain Research, vol.57, pp.1-9, 1998. ,
Variant of TREM2 associated with the risk of Alzheimer's disease, New England Journal of Medicine, vol.368, pp.107-116, 2013. ,
Analysis of fractalkine receptor CX (3)CR1 function by targeted deletion and green fluorescent protein reporter gene insertion, Molecular and Cellular Biology, vol.20, pp.4106-4114, 2000. ,
The circumventricular organs, Histology and Histopathology, vol.32, pp.879-892, 2017. ,
Microglia emerge from erythromyeloid precursors via Pu.1-and Irf8-dependent pathways, Nature Neuroscience, vol.16, pp.273-280, 2013. ,
Circulating Ly-6C1 myeloid precursors migrate to the CNS and play a pathogenic role during autoimmune demyelinating disease, Blood, vol.113, pp.3190-3197, 2009. ,
, , 2016.
, TREM2/DAP12 Signal Elicits Proinflammatory Response in Microglia and Exacerbates Neuropathic Pain, Journal of Neuroscience, vol.36, pp.11138-11150
A DAP12dependent signal promotes pro-inflammatory polarization in microglia following nerve injury and exacerbates degeneration of injured neurons, Glia, vol.63, pp.1073-1082, 2015. ,
Annexin III implicated in the microglial response to motor nerve injury, Glia, vol.53, pp.723-732, 2006. ,
Identification of peripherin as a Akt substrate in neurons, Journal of Biological Chemistry, vol.282, pp.23491-23499, 2007. ,
Siglec-h on activated microglia for recognition and engulfment of glioma cells, Glia, vol.61, pp.1122-1133, 2013. ,
Conditional rod photoreceptor ablation reveals Sall1 as a microglial marker and regulator of microglial morphology in the retina, Glia, vol.64, pp.2005-2024, 2016. ,
TNF and increased intracellular iron alter macrophage polarization to a detrimental M1 phenotype in the injured spinal cord, Neuron, vol.83, pp.1098-1116, 2014. ,
Siglec functions of microglia, Glycobiology, vol.24, pp.794-799, 2014. ,
Siglec-mediated regulation of immune cell function in disease, Nature Reviews Immunology, vol.14, pp.653-666, 2014. ,
Preserved acute pain and reduced neuropathic pain in mice lacking PKCgamma, Science, vol.278, pp.279-283, 1997. ,
P2Y12 receptor is expressed on human microglia under physiological conditions throughout development and is sensitive to neuroinflammatory diseases, Glia, vol.65, pp.375-387, 2017. ,
CCR21Ly-6Chi monocytes are crucial for the effector phase of autoimmunity in the central nervous system, Brain, vol.132, pp.2487-2500, 2009. ,
Different vascular permeability between the sensory and secretory circumventricular organs of adult mouse brain, Cell and Tissue Research, vol.349, pp.589-603, 2012. ,
Cells capable of uptake of horseradish peroxidase in some circumventricular organs of the cat and rat, Cell and Tissue Research, vol.219, pp.85-92, 1981. ,
Loss-of-function mutations in TYROBP (DAP12) result in a presenile dementia with bone cysts, Nature Genetics, vol.25, pp.357-361, 2000. ,
Mutations in two genes encoding different subunits of a receptor signaling complex result in an identical disease phenotype, American Journal of Human Genetics, vol.71, pp.656-662, 2002. ,
Synaptic pruning by microglia is necessary for normal brain development, Science, vol.333, pp.1456-1458, 2011. ,
Microglia promote learning-dependent synapse formation through brain-derived neurotrophic factor, Cell, vol.155, pp.1596-1609, 2013. ,
Genetic approaches to study glial cells in the rodent brain, Glia, vol.60, pp.681-701, 2012. ,
Ontogeny and homeostasis of CNS myeloid cells, Nature Immunology, vol.18, pp.385-392, 2017. ,
Microglia and brain macrophages in the molecular age: from origin to neuropsychiatric disease, Nature Reviews Neuroscience, vol.15, pp.300-312, 2014. ,
Heterogeneity of CNS myeloid cells and their roles in neurodegeneration, Nature Neuroscience, vol.14, pp.1227-1235, 2011. ,
Absence of Siglec-H in MCMV infection elevates interferon alpha production but does not enhance viral clearance, PLoS Pathogens, vol.9, 2013. ,
Macrophage heterogeneity in the rat as delineated by two monoclonal antibodies MRC OX-41 and MRC OX-42, the latter recognizing complement receptor type 3, Immunology, vol.57, pp.239-247, 1986. ,
Selective chemokine receptor usage by central nervous system myeloid cells in CCR2-red fluorescent protein knock-in mice, PloS One, vol.5, p.13693, 2010. ,
,
A macrophage colonystimulating factor receptor-green fluorescent protein transgene is expressed throughout the mononuclear phagocyte system of the mouse, Blood, vol.101, pp.1155-1163, 2003. ,
Microglia sculpt postnatal neural circuits in an activity and complement-dependent manner, Neuron, vol.74, pp.691-705, 2012. ,
A lineage of myeloid cells independent of Myb and hematopoietic stem cells, Science, vol.336, pp.86-90, 2012. ,
Complex invasion pattern of the cerebral cortex bymicroglial cells during development of the mouse embryo, Glia, vol.61, pp.150-163, 2013. ,
URL : https://hal.archives-ouvertes.fr/hal-01542734
Plasmacytoid dendritic cells orchestrate TLR7-mediated innate and adaptive immunity for the initiation of autoimmune inflammation, Scientific Reports, vol.6, p.24477, 2016. ,
,
Plasmacytoid dendritic cells are crucial for the initiation of inflammation and T cell immunity in vivo, Immunity, vol.35, pp.958-971, 2011. ,
URL : https://hal.archives-ouvertes.fr/hal-00665515
P2 receptors, microglial cytokines and chemokines, and neuropathic pain, Journal of Neuroscience Research, vol.95, pp.1319-1329, 2017. ,
Activating and inhibitory functions of DAP12, Nature Reviews Immunology, vol.7, pp.155-161, 2007. ,
Infiltrating monocytes promote brain inflammation and exacerbate neuronal damage after status epilepticus, vol.113, pp.5665-5674, 2016. ,
TREM2 lipid sensing sustains the microglial response in an Alzheimer's disease model, Cell, vol.160, pp.1061-1071, 2015. ,
Next generation transcriptomics and genomics elucidate biological complexity of microglia in health and disease, Glia, vol.64, pp.197-213, 2016. ,
Genetic targeting of microglia, Glia, vol.63, pp.1-22, 2015. ,
DOI : 10.1002/glia.22727
A size selective vascular barrier in the rat area postrema formed by perivascular macrophages and the extracellular matrix, Neuroscience, vol.150, pp.498-509, 2007. ,
,
Differential roles of microglia and monocytes in the inflamed central nervous system, Journal of Experimental Medicine, vol.211, pp.1533-1549, 2014. ,
Integrated systems approach identifies genetic nodes and networks in late-onset Alzheimer's disease, Cell, vol.153, pp.707-720, 2013. ,
Characterization of Siglec-H as a novel endocytic receptor expressed on murine plasmacytoid dendritic cell precursors, Blood, vol.107, pp.3600-3608, 2006. ,
Ethical guidelines for investigations of experimental pain in conscious animals, Pain, vol.16, pp.109-110, 1983. ,