title: Proinflammatory-activated glioma cells induce a switch in microglial polarization and activation status, from a predominant M2b phenotype to a mixture of M1 and M2a/B polarized cells.
abstract: Malignant gliomas are primary brain tumors characterized by morphological and genetic complexities, as well as diffuse infiltration into normal brain parenchyma. Within gliomas, microglia/macrophages represent the largest tumor-infiltrating cell population, contributing by at least one-third to the total tumor mass. Bi-directional interactions between glioma cells and microglia may therefore play an important role on tumor growth and biology. In the present study, we have characterized the influence of glioma-soluble factors on microglial function, comparing the effects of media harvested under basal conditions with those of media obtained after inducing a pro-inflammatory activation state in glioma cells. We found that microglial cells undergo a different pattern of activation depending on the stimulus; in the presence of activated glioma-derived factors, i.e. a condition mimicking the late stage of pathology, microglia presents as a mixture of polarization phenotypes (M1 and M2a/b), with up-regulation of iNOS (inducible nitric oxide synthase), ARG (arginase) and IL (interleukine)-10. At variance, microglia exposed to basal glioma-derived factors, i.e. a condition resembling the early stage of pathology, shows a more specific pattern of activation, with increased M2b polarization status and up-regulation of IL-10 only. As far as viability and cell proliferation are concerned, both LI-CM [LPS (lipopolysaccharide)-IFNγ (interferon γ) conditioned media] and C-CM (control-conditioned media) induce similar effects on microglial morphology. Finally, in human glioma tissue obtained from surgical resection of patients with IV grade glioblastoma, we detected a significant amount of CD68 positive cells, which is a marker of macrophage/microglial phagocytic activity, suggesting that in vitro findings presented here might have a relevance in the human pathology as well.
authors.affiliation: *Institute of Pharmacology, Catholic University Medical School, Rome, Italy.
authors.forename: Lucia
authors.initials: L
authors.lastname: Lisi
authors.affiliation: †Institute of Pathology, Catholic University Medical School, Rome, Italy.
authors.forename: Egidio
authors.initials: E
authors.lastname: Stigliano
authors.affiliation: †Institute of Pathology, Catholic University Medical School, Rome, Italy.
authors.forename: Libero
authors.initials: L
authors.lastname: Lauriola
authors.affiliation: *Institute of Pharmacology, Catholic University Medical School, Rome, Italy.
authors.forename: Pierluigi
authors.initials: P
authors.lastname: Navarra
authors.affiliation: *Institute of Pharmacology, Catholic University Medical School, Rome, Italy.
authors.forename: Cinzia
authors.initials: C
authors.lastname: Dello Russo
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D015703:Antigens, CD / Q000378:metabolism; D015214:Antigens, Differentiation, Myelomonocytic / Q000378:metabolism; D001119:Arginase / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects / Q000502:physiology*; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology; D017077:Culture Media, Conditioned / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D005910:Glioma / Q000378:metabolism / Q000473:pathology*; D006801:Humans; D007371:Interferon-gamma / Q000494:pharmacology; D008070:Lipopolysaccharides / Q000494:pharmacology; D017628:Microglia / Q000187:drug effects / Q000502:physiology*; D009457:Neuroglia / Q000145:classification* / Q000187:drug effects / Q000502:physiology*; D052247:Nitric Oxide Synthase Type II / Q000378:metabolism; D010641:Phenotype; D051381:Rats; D013997:Time Factors; D015854:Up-Regulation / Q000187:drug effects; D000097382:CD68 Molecule
chemical_list: D015703:Antigens, CD; D015214:Antigens, Differentiation, Myelomonocytic; D001119:Arginase; D017077:Culture Media, Conditioned; D007371:Interferon-gamma; D008070:Lipopolysaccharides; D052247:Nitric Oxide Synthase Type II; C067980:CD68 antigen, human; D000097382:CD68 Molecule