TY - JOUR
T1 - Suppressor of cytokine signaling 2 modulates the immune response profile and development of experimental cerebral malaria
AU - Brant, Fatima
AU - Miranda, Aline S.
AU - Esper, Lisia
AU - Gualdrón-López, Melisa
AU - Cisalpino, Daniel
AU - de Souza, Danielle da Gloria
AU - Rachid, Milene Alvarenga
AU - Tanowitz, Herbert B.
AU - Teixeira, Mauro Martins
AU - Teixeira, Antônio Lucio
AU - Machado, Fabiana Simão
N1 - Publisher Copyright:
© 2016 Elsevier Inc.
PY - 2016/5/1
Y1 - 2016/5/1
N2 - Plasmodium falciparum infection results in severe malaria in humans, affecting various organs, including the liver, spleen and brain, and resulting in high morbidity and mortality. The Plasmodium berghei ANKA (PbA) infection in mice closely recapitulates many aspects of human cerebral malaria (CM); thus, this model has been used to investigate the pathogenesis of CM. Suppressor of cytokine signaling 2 (SOCS2), an intracellular protein induced by cytokines and hormones, modulates the immune response, neural development, neurogenesis and neurotrophic pathways. However, the role of SOCS2 during CM remains unknown. SOCS2 knockout (SOCS2-/-) mice infected with PbA show an initial resistance to infection with reduced parasitemia and production of TNF, TGF-β, IL-12 and IL-17 in the brain. Interestingly, in the late phase of infection, SOCS2-/- mice display increased parasitemia and reduced Treg cell infiltration, associated with enhanced levels of Th1 and Th17 cells and related cytokines IL-17, IL-6, and TGF-β in the brain. A significant reduction in protective neurotrophic factors, such as glial cell line-derived neurotrophic factor (GDNF) and brain-derived neurotrophic factor (BDNF), was also observed. Moreover, the molecular alterations in the brain of infected SOCS2-/- mice were associated with anxiety-related behaviors and cognition impairment. Mechanistically, these results revealed enhanced nitric oxide (NO) production in PbA-infected SOCS2-/- mice, and the inhibition of NO synthesis through l-NAME led to a marked decrease in survival, the disruption of parasitemia control and more pronounced anxiety-like behavior. Treatment with l-NAME also shifted the levels of Th1, Th7 and Treg cells in the brains of infected SOCS2-/- mice to the background levels observed in infected WT, with remarkable exception of increased CD8+IFN+ T cells and inflammatory monocytes. These results indicate that SOCS2 plays a dual role during PbA infection, being detrimental in the control of the parasite replication but crucial in the regulation of the immune response and production of neurotrophic factors. Here, we provided strong evidence of a critical relationship between SOCS2 and NO in the orchestration of the immune response and development of CM during PbA infection.
AB - Plasmodium falciparum infection results in severe malaria in humans, affecting various organs, including the liver, spleen and brain, and resulting in high morbidity and mortality. The Plasmodium berghei ANKA (PbA) infection in mice closely recapitulates many aspects of human cerebral malaria (CM); thus, this model has been used to investigate the pathogenesis of CM. Suppressor of cytokine signaling 2 (SOCS2), an intracellular protein induced by cytokines and hormones, modulates the immune response, neural development, neurogenesis and neurotrophic pathways. However, the role of SOCS2 during CM remains unknown. SOCS2 knockout (SOCS2-/-) mice infected with PbA show an initial resistance to infection with reduced parasitemia and production of TNF, TGF-β, IL-12 and IL-17 in the brain. Interestingly, in the late phase of infection, SOCS2-/- mice display increased parasitemia and reduced Treg cell infiltration, associated with enhanced levels of Th1 and Th17 cells and related cytokines IL-17, IL-6, and TGF-β in the brain. A significant reduction in protective neurotrophic factors, such as glial cell line-derived neurotrophic factor (GDNF) and brain-derived neurotrophic factor (BDNF), was also observed. Moreover, the molecular alterations in the brain of infected SOCS2-/- mice were associated with anxiety-related behaviors and cognition impairment. Mechanistically, these results revealed enhanced nitric oxide (NO) production in PbA-infected SOCS2-/- mice, and the inhibition of NO synthesis through l-NAME led to a marked decrease in survival, the disruption of parasitemia control and more pronounced anxiety-like behavior. Treatment with l-NAME also shifted the levels of Th1, Th7 and Treg cells in the brains of infected SOCS2-/- mice to the background levels observed in infected WT, with remarkable exception of increased CD8+IFN+ T cells and inflammatory monocytes. These results indicate that SOCS2 plays a dual role during PbA infection, being detrimental in the control of the parasite replication but crucial in the regulation of the immune response and production of neurotrophic factors. Here, we provided strong evidence of a critical relationship between SOCS2 and NO in the orchestration of the immune response and development of CM during PbA infection.
KW - BDNF
KW - Cerebral malaria
KW - GDNF
KW - Immune regulation
KW - L-NAME
KW - Neuroimmune response
KW - Neuroinflammation
KW - Neurotrophic factors
KW - Nitric oxide
KW - SOCS2
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UR - http://www.scopus.com/inward/citedby.url?scp=84954287766&partnerID=8YFLogxK
U2 - 10.1016/j.bbi.2016.01.002
DO - 10.1016/j.bbi.2016.01.002
M3 - Article
C2 - 26765997
AN - SCOPUS:84954287766
SN - 0889-1591
VL - 54
SP - 73
EP - 85
JO - Brain, Behavior, and Immunity
JF - Brain, Behavior, and Immunity
ER -