Role of programmed death ligand 2 in macrophage activation during Fasciola hepatica infection

STEMPIN, CC; FALCON, CR; AOKI, MP; MOTRAN, CC; CERBAN, FM; CERVI

Mar del PLata

Congreso; LIX Reunión Científica Anual de la Sociedad Argentina de Investigación Clínica, LXII Reunión Científica Anual de la Sociedad Argentina de Inmunología; 2014

Helminth infections induce an increase in co-inhibitory molecule programmed death ligand-2 (PD-L2) which is defined as a marker for alternatively activated macrophages and is involved in the inhibition of T cell proliferation. However, it is not known how PD-L2 modulates macrophage activation, which promotes fibrosis in helminth infections, whereas classical activation produces deleterious toxic metabolites. Previously we have observed that F. hepatica infection increases PD-L2 expression in F4/80+ cells. The aim of this study was to investigate the role of PD-L2 in the outcome of F. hepatica infection as well as in macrophage activation during experimental infection with the parasite. BALB/c WT and PD-L2 KO were orally infected with 8 F. hepatica metacercariae. Survival rate was evaluated and histological changes in liver tissues were determined by hematoxylin and eosin staining. PD-L2 KO mice showed increased mortality during F. hepatica infection (p<0.05). Histological analysis of infected liver from WT and PD-L2 KO mice showed tissue damage, being greater extent in PD-L2 KO mice. Fasciolosis, like other helminth infections, is associated with the induction of T-cell responses polarized to the Th2 subtype. Spleen mononuclear cells (SMC) from WT infected mice exhibited a polarized Th2 cytokine profile in response to F. hepatica antigens while SMC from PD-L2 infected mice showed a predominant Th1 response. On the other hand, to study macrophage activation, peritoneal cells (PC) were obtained at different time point of infection (24, 48 and 72 hs p.i) and stimulated with LPS plus INF or IL4 during 24 hs. Arginase activity and nitrite production were evaluated. The results show that, PC from PD-L2 KO infected mice exhibit reduced arginase activity and nitrite production at 24 hs p.i. Our data indicate that PD-L2 is involved in arginase/iNOS activation in macrophages which may play a protective role during F. hepatica infection.