Activation of TNF receptor 2 in microglia promotes induction of anti-inflammatory pathways.
Fine regulation of the innate immune response following brain injury or infection is important to avoid excessive activation of microglia and its detrimental consequences on neural cell viability and function. To get insights on the molecular networks regulating microglia activation, we analyzed expression, regulation and functional relevance of tumor necrosis factor receptors (TNFR) 2 in cultured mouse microglia. We found that microglia upregulate TNFR2 mRNA and protein and shed large amounts of soluble TNFR2, but not TNFR1, in response to pro-inflammatory stimuli and through activation of TNFR2 itself. By microarray analysis, we demonstrate that TNFR2 stimulation in microglia regulates expression of genes involved in immune processes, including molecules with anti-inflammatory and neuroprotective function like granulocyte colony-stimulating factor, adrenomedullin and IL-10. In addition, we identify IFN-γ as a regulator of the balance between pro- and anti-inflammatory/neuroprotective factors induced by TNFR2 stimulation. These data indicate that, through TNFR2, microglia may contribute to the counter-regulatory response activated in neuropathological conditions.
Veroni
Caterina
C
Departments of Cell Biology and Neurosciences, Istituto Superiore di Sanità, Viale Regina Elena 299, 00161 Rome, Italy.
Gabriele
Lucia
L
Canini
Irene
I
Castiello
Luciano
L
Coccia
Eliana
E
Remoli
Maria Elena
ME
Columba-Cabezas
Sandra
S
Aricò
Eleonora
E
Aloisi
Francesca
F
Agresti
Cristina
C
D000818:Animals; D002478:Cells, Cultured; D005786:Gene Expression Regulation; D016179:Granulocyte Colony-Stimulating Factor / Q000378:metabolism; D007249:Inflammation / Q000276:immunology*; D007371:Interferon-gamma / Q000276:immunology; D016753:Interleukin-10 / Q000378:metabolism; D051379:Mice; D046228:Microarray Analysis; D017628:Microglia / Q000166:cytology / Q000378:metabolism*; D047888:Receptors, Tumor Necrosis Factor, Type I / Q000235:genetics / Q000378:metabolism; D047889:Receptors, Tumor Necrosis Factor, Type II / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
D047888:Receptors, Tumor Necrosis Factor, Type I; D047889:Receptors, Tumor Necrosis Factor, Type II; D014409:Tumor Necrosis Factor-alpha; D016753:Interleukin-10; D016179:Granulocyte Colony-Stimulating Factor; D007371:Interferon-gamma