title: Microglia are less pro-inflammatory than myeloid infiltrates in the hippocampus of mice exposed to status epilepticus.
abstract: Activated microglia, astrogliosis, expression of pro-inflammatory cytokines, blood brain barrier (BBB) leakage and peripheral immune cell infiltration are features of mesial temporal lobe epilepsy. Numerous studies correlated the expression of pro-inflammatory cytokines with the activated morphology of microglia, attributing them a pro-epileptogenic role. However, microglia and myeloid cells such as macrophages have always been difficult to distinguish due to an overlap in expressed cell surface molecules. Thus, the detrimental role in epilepsy that is attributed to microglia might be shared with myeloid infiltrates. Here, we used a FACS-based approach to discriminate between microglia and myeloid infiltrates isolated from the hippocampus 24 h and 96 h after status epilepticus (SE) in pilocarpine-treated CD1 mice. We observed that microglia do not express MHCII whereas myeloid infiltrates express high levels of MHCII and CD40 96 h after SE. This antigen-presenting cell phenotype correlated with the presence of CD4(pos) T cells. Moreover, microglia only expressed TNFα 24 h after SE while myeloid infiltrates expressed high levels of IL-1β and TNFα. Immunofluorescence showed that astrocytes but not microglia expressed IL-1β. Myeloid infiltrates also expressed matrix metalloproteinase (MMP)-9 and 12 while microglia only expressed MMP-12, suggesting the involvement of both cell types in the BBB leakage that follows SE. Finally, both cell types expressed the phagocytosis receptor Axl, pointing to phagocytosis of apoptotic cells as one of the main functions of microglia. Our data suggests that, during early epileptogenesis, microglia from the hippocampus remain rather immune supressed whereas myeloid infiltrates display a strong inflammatory profile. GLIA 2016 GLIA 2016;64:1350-1362.
authors.affiliation: Department of Biomedical, Metabolic and Neural Sciences, University of Modena and Reggio Emilia, via G. Campi, 287, Modena, Italy.
authors.forename: Jonathan
authors.initials: J
authors.lastname: Vinet
authors.affiliation: Department of Neuroscience, Section Medical Physiology, University Medical Center Groningen, University of Groningen, Antonius Deusinglaan, 1, Groningen, The Netherlands.
authors.forename: Ilia D
authors.initials: ID
authors.lastname: Vainchtein
authors.affiliation: Laboratory of Cell Therapies, Department of Medical and Surgical Sciences for Children & Adults, University Hospital of Modena and Reggio Emilia, via Del Pozzo, 71, Modena, Italy.
authors.forename: Carlotta
authors.initials: C
authors.lastname: Spano
authors.affiliation: Department of Biomedical, Metabolic and Neural Sciences, University of Modena and Reggio Emilia, via G. Campi, 287, Modena, Italy.
authors.forename: Carmela
authors.initials: C
authors.lastname: Giordano
authors.affiliation: Department of Biomedical, Metabolic and Neural Sciences, University of Modena and Reggio Emilia, via G. Campi, 287, Modena, Italy.
authors.forename: Domenico
authors.initials: D
authors.lastname: Bordini
authors.affiliation: Department of Biomedical, Metabolic and Neural Sciences, University of Modena and Reggio Emilia, via G. Campi, 287, Modena, Italy.
authors.forename: Giulia
authors.initials: G
authors.lastname: Curia
authors.affiliation: Laboratory of Cell Therapies, Department of Medical and Surgical Sciences for Children & Adults, University Hospital of Modena and Reggio Emilia, via Del Pozzo, 71, Modena, Italy.
authors.forename: Massimo
authors.initials: M
authors.lastname: Dominici
authors.affiliation: Department of Neuroscience, Section Medical Physiology, University Medical Center Groningen, University of Groningen, Antonius Deusinglaan, 1, Groningen, The Netherlands.
authors.forename: Hendrikus W G M
authors.initials: HW
authors.lastname: Boddeke
authors.affiliation: Department of Neuroscience, Section Medical Physiology, University Medical Center Groningen, University of Groningen, Antonius Deusinglaan, 1, Groningen, The Netherlands.
authors.forename: Bart J L
authors.initials: BJ
authors.lastname: Eggen
authors.affiliation: Department of Biomedical, Metabolic and Neural Sciences, University of Modena and Reggio Emilia, via G. Campi, 287, Modena, Italy.
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Biagini
mesh_terms: D000818:Animals; D001253:Astrocytes / Q000276:immunology / Q000473:pathology; D019013:CD40 Antigens / Q000378:metabolism; D004195:Disease Models, Animal; D006624:Hippocampus / Q000276:immunology* / Q000473:pathology; D053583:Interleukin-1beta / Q000378:metabolism; D008297:Male; D053508:Matrix Metalloproteinase 12 / Q000378:metabolism; D020780:Matrix Metalloproteinase 9; D051379:Mice; D017628:Microglia / Q000276:immunology* / Q000473:pathology; D022423:Myeloid Cells / Q000276:immunology* / Q000473:pathology; D010862:Pilocarpine; D066195:Piriform Cortex / Q000276:immunology / Q000473:pathology; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D020794:Receptor Protein-Tyrosine Kinases / Q000378:metabolism; D013226:Status Epilepticus / Q000276:immunology* / Q000473:pathology; D000094963:Axl Receptor Tyrosine Kinase
chemical_list: D019013:CD40 Antigens; C587672:IL1B protein, mouse; D053583:Interleukin-1beta; D011518:Proto-Oncogene Proteins; D010862:Pilocarpine; D020794:Receptor Protein-Tyrosine Kinases; D020780:Matrix Metalloproteinase 9; C501830:Mmp9 protein, mouse; D053508:Matrix Metalloproteinase 12; C000602031:matrix metallopeptidase 12, mouse; D000094963:Axl Receptor Tyrosine Kinase; C000722290:AXL receptor tyrosine kinase, mouse
keywords: epileptogenesis; metalloproteinases; pilocarpine; pro-inflammatory cytokines; temporal lobe epilepsy