Soluble factors released by Toxoplasma gondii-infected astrocytes down-modulate nitric oxide production by gamma interferon-activated microglia and prevent neuronal degeneration.
The maintenance of a benign chronic Toxoplasma gondii infection is mainly dependent on the persistent presence of gamma interferon (IFN-gamma) in the central nervous system (CNS). However, IFN-gamma-activated microglia are paradoxically involved in parasitism control and in tissue damage during a broad range of CNS pathologies. In this way, nitric oxide (NO), the main toxic metabolite produced by IFN-gamma-activated microglia, may cause neuronal injury during T. gondii infection. Despite the potential NO toxicity, neurodegeneration is not a common finding during chronic T. gondii infection. In this work, we describe a significant down-modulation of NO production by IFN-gamma-activated microglia in the presence of conditioned medium of T. gondii-infected astrocytes (CMi). The inhibition of NO production was paralleled with recovery of neurite outgrowth when neurons were cocultured with IFN-gamma-activated microglia in the presence of CMi. Moreover, the modulation of NO secretion and the neuroprotective effect were shown to be dependent on prostaglandin E(2) (PGE(2)) production by T. gondii-infected astrocytes and autocrine secretion of interleukin-10 (IL-10) by microglia. These events were partially eliminated when infected astrocytes were treated with aspirin and cocultures were treated with anti-IL-10 neutralizing antibodies and RP-8-Br cyclic AMP (cAMP), a protein kinase A inhibitor. Further, the modulatory effects of CMi were mimicked by the presence of exogenous PGE(2) and by forskolin, an adenylate cyclase activator. Altogether, these data point to a T. gondii-triggered regulatory mechanism involving PGE(2) secretion by astrocytes and cAMP-dependent IL-10 secretion by microglia. This may reduce host tissue inflammation, thus avoiding neuron damage during an established Th1 protective immune response.
Rozenfeld
Claudia
C
Instituto de Biofísica Carlos Chagas Filho, Departamento de Anatomia, ICB, Universidade Federal do Rio de Janeiro, Rio de Janeiro 21944-590, Brazil. rozen@biof.ufrj.br
Martinez
Rodrigo
R
Figueiredo
Rodrigo T
RT
Bozza
Marcelo T
MT
Lima
Flávia R S
FR
Pires
Ana Lúcia
AL
Silva
Patrícia M
PM
Bonomo
Adriana
A
Lannes-Vieira
Joseli
J
De Souza
Wanderley
W
Moura-Neto
Vivaldo
V
D000818:Animals; D001253:Astrocytes / Q000276:immunology* / Q000469:parasitology; D002478:Cells, Cultured; D018920:Coculture Techniques; D017077:Culture Media, Conditioned / Q000494:pharmacology*; D000242:Cyclic AMP / Q000096:biosynthesis; D015232:Dinoprostone / Q000096:biosynthesis; D015536:Down-Regulation / Q000187:drug effects; D007371:Interferon-gamma / Q000276:immunology; D016753:Interleukin-10 / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D017628:Microglia / Q000187:drug effects* / Q000276:immunology; D009474:Neurons / Q000276:immunology* / Q000473:pathology; D009569:Nitric Oxide / Q000096:biosynthesis*; D012995:Solubility; D014122:Toxoplasma / Q000472:pathogenicity*
D017077:Culture Media, Conditioned; D016753:Interleukin-10; D009569:Nitric Oxide; D007371:Interferon-gamma; D000242:Cyclic AMP; D015232:Dinoprostone