Inducible Nitric Oxide Synthase and Arginase Expression in Heart Tissue during AcuteTrypanosoma cruziInfection in Mice: Arginase I Is Expressed in Infiltrating CD68⁺Macrophages

Abstract

In Chagas disease, which is caused by Trypanosoma cruzi, macrophages and cardiomyocytes are the main targets of infection. Classical activation of macrophages during infection is protective, whereas alternative activation of macrophages is involved in the survival of host cells and parasites. We studied the expression of inducible nitric oxide synthase (iNOS) and arginase as markers of classical and alternative activation, respectively, in heart tissue during in vivo infection of BALB/c and C57BL/6 mice. We found that expression of arginase I and II, as well as that of ornithine decarboxylase, was much higher in BALB/c mice than in C57BL/6 mice and that it was associated with the parasite burden in heart tissue. iNOS and arginase II were expressed by cardiomyocytes. Interestingly, heart-infiltrated CD68+ macrophages were the major cell type expressing arginase I. T helper (Th) 1 and Th2 cytokines were expressed in heart tissue in both infected mouse strains; however, at the peak of parasite infection, the balance between Th1 and Th2 predominantly favored Th1 in C57BL/6 mice and Th2 in BALB/c mice. The results of the present study suggest that Th2 cytokines induce arginase expression, which may influence host and parasite cell survival but which might also down-regulate the counterproductive effects triggered by iNOS in the heart during infection.

Myeloid-Derived Suppressor Cells Infiltrate the Heart in Acute Trypanosoma cruzi Infection

“…We also detected arginase I expression in CD11b + Ly6G 2 cells isolated from the blood of infected mice but not from noninfected mice (Fig. 5B), in agreement with previous observations in PBMC lysates (19). CD11b + Ly6G 2 cells, but not Ly6G + cells, from hearts of infected mice suppressed anti-CD3/anti-CD28-stimulated T cell proliferation in comparison with T cells alone and T cells cultured with CD11b + NI (Fig.…”

“…Coinciding with the presence of monocytic MDSCs, our results showed that S100a8 and S100a9 gene and corresponding protein expression (Fig. 6A and 6B, respectively) were detected in heart tissue in the acute phase of T. cruzi infection in BALB/c mice, showing highest expression at 21 dpi coincident with previously described maximum arginase I and iNOS expression (19). We also detected expression of S100a8 and S100a9 gene and protein in C57BL/6 infected mice (Supplemental Fig.…”

“…We previously described a population of myeloid cells expressing arginase I infiltrating the hearts of mice during acute T. cruzi infection (19). To characterize further the myeloid-infiltrating cells, CD11b + populations from hearts of infected mice (HI) were isolated at the time in which arginase I heart tissue expression was maximal [14 d postinfection (dpi) and 21 dpi in C57BL/6 and BALB/c mice, respectively] (19).…”

“…We have previously reported the existence of a population of infiltrating myeloid cells expressing arginase I in the hearts of mice during the acute phase of Chagas disease (19). The aim of this work was to characterize the heart-infiltrating myeloid CD11b + cells in acute T. cruzi infection.…”

Trypanosoma cruzi strains cause different myocarditis patterns in infected mice

“…Quantitative RT-PCR analysis was performed using the High Capacity cDNA Archive Kit (Applied Biosystems) and different genes (Ifng,Tnf,il4,il10,il13,il12,ptgs2 and 18S rRNA) were amplified in triplicate using TaqMan MGB probes and the TaqMan Universal PCR Master Mix (Applied Biosystems) on an ABI PRISM 7900 HT instrument (Applied Biosystems) as previously described (Cuervo et al, 2008). Parasite DNA and gene expression by real-time PCR was quantified by the comparative threshold cycle (CT) method (RQ 2 -C T), using normalization by the 18S ribosomal endogenous control levels and reported to uninfected control animals.…”