Role of SOCS2 in modulating heart damage and function in a murine model of acute Chagas disease.
Infection with Trypanosoma cruzi induces inflammation, which limits parasite proliferation but may result in chagasic heart disease. Suppressor of cytokine signaling 2 (SOCS2) is a regulator of immune responses and may therefore participate in the pathogenesis of T. cruzi infection. SOCS2 is expressed during T. cruzi infection, and its expression is partially reduced in infected 5-lipoxygenase-deficient [knockout (KO)] mice. In SOCS2 KO mice, there was a reduction in both parasitemia and the expression of interferon-γ (IFN-γ), tumor necrosis factor-α (TNF-α), IL-6, IL-10, SOCS1, and SOCS3 in the spleen. Expression of IFN-γ, TNF-α, SOCS1, and SOCS3 was also reduced in the hearts of infected SOCS2 KO mice. There was an increase in the generation and expansion of T regulatory (Treg) cells and a decrease in the number of memory cells in T. cruzi-infected SOCS2 KO mice. Levels of lipoxinA(4) (LXA(4)) increased in these mice. Echocardiography studies demonstrated an impairment of cardiac function in T. cruzi-infected SOCS2 KO mice. There were also changes in calcium handling and in action potential waveforms, and reduced outward potassium currents in isolated cardiac myocytes. Our data suggest that reductions of inflammation and parasitemia in infected SOCS2-deficient mice may be secondary to the increases in Treg cells and LXA(4) levels. This occurs at the cost of greater infection-associated heart dysfunction, highlighting the relevance of balanced inflammatory and immune responses in preventing severe T. cruzi-induced disease.
Department of Biochemistry and Immunology, Institute of Biological Science, Federal University of Minas Gerais, Belo Horizonte, Brazil.
Lisia
L
Esper
Danilo
D
Roman-Campos
Aline
A
Lara
Fatima
F
Brant
Luisa L
LL
Castro
Andreia
A
Barroso
Ronan Ricardo S
RR
Araujo
Leda Q
LQ
Vieira
Shankar
S
Mukherjee
Eneas Ricardo M
ER
Gomes
Nazareth N
NN
Rocha
Isalira P R
IP
Ramos
Michael P
MP
Lisanti
Camila F
CF
Campos
Rosa M E
RM
Arantes
Silvia
S
Guatimosim
Louis M
LM
Weiss
Jader Santos
JS
Cruz
Herbert B
HB
Tanowitz
Mauro M
MM
Teixeira
Fabiana S
FS
Machado
D000208:Acute Disease; D000818:Animals; D001094:Arachidonate 5-Lipoxygenase / Q000502:physiology; D002478:Cells, Cultured; D002598:Chagas Cardiomyopathy / Q000276:immunology* / Q000469:parasitology / Q000473:pathology / Q000503:physiopathology; D016207:Cytokines / Q000096:biosynthesis; D004195:Disease Models, Animal; D006321:Heart / Q000469:parasitology; D044045:Lipoxins / Q000378:metabolism; D008264:Macrophages / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D032383:Myocytes, Cardiac / Q000276:immunology; D059208:Parasite Load; D018512:Parasitemia / Q000276:immunology; D018408:Patch-Clamp Techniques; D050826:Suppressor of Cytokine Signaling Proteins / Q000172:deficiency / Q000276:immunology*; D016176:T-Lymphocyte Subsets / Q000276:immunology; D014349:Trypanosoma cruzi / Q000302:isolation & purification
D016207:Cytokines; D044045:Lipoxins; C491409:Socs2 protein, mouse; D050826:Suppressor of Cytokine Signaling Proteins; C040527:lipoxin A4; D001094:Arachidonate 5-Lipoxygenase