BackgroundLeishmania preferentially infects macrophages, which allow the parasite to multiply but can also kill the parasite. Although the T cell response in human leishmaniasis is well-characterized, little is known about the concomitant macrophage behavior. The aim of this study was to characterize the macrophage immune response after Leishmania braziliensis infection in cells derived from cutaneous leishmaniasis (CL) or mucosal leishmaniasis (ML) patients, subclinical individuals (SC) and healthy control subjects (HS).MethodsPeripheral blood mononuclear cell-derived macrophages from the different groups were exposed to L. braziliensis in vitro and were evaluated for susceptibility to Leishmania infection, ability to kill Leishmania and chemokine/cytokine production. Nitric Oxide (NO) and superoxide (O2-) levels in the supernatant of infected macrophage cultures were monitored.ResultsAfter exposure to L. braziliensis, peripheral blood mononuclear cell-derived macrophages from SC individuals showed a lower infection rate and a smaller number of intracellular amastigotes compared to cells from CL and ML patients. Macrophages from CL and ML patients produced more chemokines and TNF-α than those from the SC group. Production of NO and O2- were detected but did not vary significantly among the different groups.ConclusionsOur data indicate that macrophages play a pivotal role in controlling L. braziliensis infection and in leishmaniasis pathology by secreting pro-inflammatory chemokines/cytokines that activate and recruit T cells, overwhelming the inflammatory response.
We showed previously that insulin‐like growth factor (IGF)‐I induces an exacerbation of the lesion development in experimental cutaneous leishmaniasis favouring parasite growth within host macrophages. Here we studied the effect of IGF‐I in vitro in BALB/c mouse peritoneal macrophages infected with stationary phase Leishmania amazonensis promastigotes. IGF‐I was used to pre‐incubate either macrophage or parasite before infection of the macrophages or adding it at the start of the Leishmania–macrophage culture and maintaining it throughout the experimental period. Independent of stimulation protocol, IGF‐I induced significantly increased parasite growth within macrophages. Arginase activation considered as a key factor in Leishmania growth was studied, and its expression and activity were increased in Leishmania‐infected macrophages but significantly more in infected cells upon IGF‐I stimulus, an effect specifically inhibited by NOHA. Arginase known to be present on Leishmania was also studied, and its expression and activity were seen in the absence of any stimulus but significantly increased after 5 min of incubation with IGF‐I. In addition, Leishmania was pre‐incubated with NOHA for 5 min, washed, then macrophages infected observing a significantly reduced parasite burden in both IGF‐I‐stimulated and non‐stimulated macrophages. Reciprocal decrease in the nitric oxide (NO) level and inhibition of nitric oxide synthase (NOS2) expression were also observed in IGF‐I‐stimulated infected macrophages. Our data strongly suggest that IGF‐I induces preferential expression and activation of Leishmania promastigote arginase, contributes to the alternative activation of macrophages in the context of innate immunity and interferes with NOS pathway in infected macrophages probably as a reciprocal effect.
Arginase activity has been related to leishmaniasis development, thus we studied the constitutive and insulin-like growth factor (IGF) I-induced arginase activity of Leishmania (Viannia) braziliensis isolates from patients with different clinical forms of American tegumentary leishmaniasis (ATL). Isolates from mucosal leishmaniasis presented higher basal levels of arginase activity than isolates from other clinical forms of ATL. Isolates from disseminated leishmaniasis that present mucosal lesion in some cases reached the arginase activity similar to that of isolates from mucosal leishmaniasis upon IGF-I stimulation. Differences in arginase activity may influence disease outcomes such as evolution to mucosal lesion in patients with L. (V.) braziliensis infection.
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