The influence of low oxygen on macrophage response to Leishmania infection.

Hypoxia (low oxygen tension) is a common feature of inflamed and infected tissues. The influence of hypoxia on macrophage responses to micro-organisms has only recently been studied. This study demonstrates that hypoxia induced macrophages to control Leishmania amazonensis, an intracellular parasite that causes cutaneous and cutaneous metastatic lesions. The mechanisms that contribute to the control of macrophages against L. amazonensis infection under a hypoxic microenvironment are not known. Nitric oxide, TNF-α, IL-10 or IL-12 is not responsible for the decrease in parasitism under hypoxia. Live L. amazonensis entry or exocytosis of internalized particles as well as energetic metabolism was not impaired in infected macrophages; no apoptosis-like death was detected in intracellular parasites. Reactive oxygen species (ROS) is likely to be involved, because treatment with antioxidants N-acetylcysteine (NAC) and ebselen inhibits the leishmanicidal effect of macrophages under hypoxia. Leishmania amazonensis infection induces macrophages to express hypoxia-inducible factor-1 (HIF-1α) and -2 (HIF-2α). Data indicate that hypoxia affects the microbial activities and protein expression of macrophages leading to a different phenotype from that of the normoxic counterpart and that it plays a role in modulating Leishmania infection.

Degrossoli A ，Arrais-Silva WW ，Colhone MC ，Gadelha FR ，Joazeiro PP ，Giorgio S ... -  《-》

Infection by Leishmania amazonensis in mice: a potential model for chronic hypoxia.

Hypoxia is a common feature of injured and infected tissues. Hypoxia inducible factors 1α and 2α (HIF-1α, HIF-2α) are heterodimeric transcription factors mediating the cellular responses to hypoxia and also the vascular endothelial growth factor (VEGF). VEGF is a cytokine which can be induced by hypoxia, whose pathogenic mechanisms are still unclear and which is the subject of debate. Murine cutaneous lesions during Leishmania amazonensis parasite infection are chronic, although they are small and self-controlled in C57BL/6 mice and severe in BALB/c mice. In the present study we examined the presence of hypoxia, HIF-1α, HIF-2α and VEGF during the course of infection in both mouse strains. Hypoxia was detected in lesions from BALB/c mice by pimonidazole marking, which occurred earlier than in lesions from C57Bl/6 mice. The lesions in the BALB/c mice showed HIF-1α and HIF-2α expression in the cytoplasm of macrophages and failed to promote any VEGF expression, while lesions in the C57BL/6 mice showed HIF-2α nuclear accumulation and subsequent VEGF expression. In conclusion, the animal models of leishmaniasis demonstrated a diversity of patterns of expression, cell localization and activity of the main transducers of hypoxia and may be useful models for studying the pathogenic mechanisms of HIF-1α and HIF-2α during chronic hypoxic diseases.

Araújo AP ，Arrais-Silva WW ，Giorgio S 《-》

HIF-1α-regulated MIF activation and Nox2-dependent ROS generation promote Leishmania amazonensis killing by macrophages under hypoxia.

Increasing attention is given to the finding that macrophages under hypoxia are capable of controlling infection by the intracellular protozoan parasite Leishmania amazonensis. The hypoxia-inducible factor (HIF)-1α has been shown to play an essential role in this enhanced innate immune response. Our study aimed to explore the HIF-1α-dependent mechanisms leading to reduced survival of the parasites residing in macrophages under low oxygen conditions. Hypoxia triggered (P < 0.01) NADPH oxidase 2 (Nox2) expression and reactive oxygen species (ROS) production in J774 macrophages upon 24-h infection with L. amazonensis. Furthermore, increased (P < 0.01) expression levels of HIF-1α and macrophage migration inhibitory factor (MIF) were detected in the infected cells grown at 3% oxygen tension. We found that either HIF-1α silencing, Nox2 inhibition or MIF antagonism caused a significant (P < 0.05) reversal of the improved leishmanicidal activity displayed by the hypoxic phagocytes. Taken together, our current results suggest that, under conditions of limited availability of oxygen, activation of the HIF-1α/MIF axis via Nox2/ROS induction promotes killing of L. amazonensis amastigotes by macrophages. Such protective mechanism might operate in L. amazonensis-infected tissues where low oxygen levels prevail.

Alonso D ，Serrano E ，Bermejo FJ ，Corral RS ... -  《-》

Expression of hypoxia-inducible factor-1alpha in the cutaneous lesions of BALB/c mice infected with Leishmania amazonensis.

Arrais-Silva WW ，Paffaro VA Jr ，Yamada AT ，Giorgio S ... -  《EXPERIMENTAL AND MOLECULAR PATHOLOGY》

Cytokines, signaling pathways, and effector molecules required for the control of Leishmania (Viannia) braziliensis in mice.

Rocha FJ ，Schleicher U ，Mattner J ，Alber G ，Bogdan C ... -  《-》