Induction of hemeoxygenase-1 (Ho-1) by phagocytosis of apoptotic cells is a critical modulator of Trypanosoma cruzi infection

Abstract

Apoptotic cells are rapidly recognized and engulfed by professional phagocytes such as macrophages to avoid secondary necrosis and thus inflammation. Recognition of apoptotic cells polarizes macrophages toward an anti-inflammatory phenotype. However, mechanistic details provoking these phenotype alterations are incompletely understood. Previously our group has shown that there is intense lymphocyte apoptosis in an experimental model of Chagas' disease, a debilitating cardiac illness caused by the protozoan Trypanosoma cruzi. Here, we demonstrated a biphasic up-regulation of heme oxygenase-1 (HO-1), a protein that bears an anti-inflammatory potential, in infected murine macrophages, which were exposed to the apoptotic cells. The induction of HO-1 by apoptotic cell uptake or with single treatment with of the HO-1 inducer cobalt protoporphyrin (CoPPIX) correlated with increased number of infected macrophages and number of viable trypomastigote released. Also, induction of HO-1 correlated with increased production of anti-inflammatory factors (TGF-β and PGE-2), and decreased production of TNF-α and nitric oxide (NO). Infected macrophages cocultured with apoptotic cells in the presence of the HO-1 inhibitor tin-protoporphyrin IX (SnPPIX) drastically reduced the numbers of infected cells and trypomastigotes released. These results suggested that induction of HO-1 by uptake of apoptotic cells is a critical modulator of T. cruzi infection.