Immunohistochemical evidence of stress and inflammatory markers in mouse models of cutaneous leishmaniosis

Abstract

Leishmanioses are chronic parasitic diseases and host responses are associated with pro- or anti-inflammatory cytokines involved, respectively, in the control or exacerbation of infection. The relevance of other inflammatory mediators and stress markers has not been widely studied and there is a need to search for biomarkers to leishmaniasis. In this work, the stress and inflammatory molecules p38 mitogen-activated protein kinase, cyclooxygenase-2, migration inhibitory factor, macrophage inflammatory protein 2, heat shock protein 70 kDa, vascular endothelial factor (VEGF), hypoxia-inducible factors (HIF-1α and HIF-2α), heme oxygenase and galectin-3 expression were assessed immunohistochemically in self-controlled lesions in C57BL/6 mice and severe lesions in Balb/c mice infected with Leishmania amazonensis. The results indicated that the majority of molecules were expressed in the cutaneous lesions of both C57BL/6 and Balb/c mice during various phases of infection, suggesting no obvious correlation between the stress and inflammatory molecule expression and the control/exacerbation of leishmanial lesions. However, the cytokine VEGF was only detected in C57BL/6 footpad lesions and small lesions in Balb/c mice treated with antimonial pentavalent. These findings suggest that VEGF expression could be a predictive factor for murine leishmanial control, a hypothesis that should be tested in human leishmaniosis.

Leishmania Infection Induces Macrophage Vascular Endothelial Growth Factor A Production in an ARNT/HIF-Dependent Manner

“…In addition to hypoxia, proinflammatory cytokines and Toll-like receptor (TLR) signaling can also activate HIF-1␣ (21). Similarly to VEGF-A during Leishmania infection, HIF-1␣ is expressed in the skin (11,14,22,23). The site of Leishmania infection is hypoxic, which may lead to HIF-1␣ activation (14,24).…”

“…Similarly to VEGF-A during Leishmania infection, HIF-1␣ is expressed in the skin (11,14,22,23). The site of Leishmania infection is hypoxic, which may lead to HIF-1␣ activation (14,24). Alternatively, Leishmania major, Leishmania amazonensis, and Leishmania donovani can directly induce HIF activation, and this response is amplified in the presence of proinflammatory stimuli (22,(25)(26)(27).…”

HSP70 of Leishmania amazonensis alters resistance to different stresses and mitochondrial bioenergetics

“…To date, studies have focused on the L. amazonensis sequence and genomic organisation of HSP70, as well as its identification ( Teixeira et al 2015 ) and detection ( Araújo & Giorgio 2015 ). The biological role of HSP70 in this parasite species and its involvement in energy metabolism has not yet been investigated.…”

“…No studies have examined the potential effect of HSP70 on energy metabolism. Although the sequence and genomic organisation of the HSP70 gene ( Bock & Langer 1993 ), the protein’s identification using immunohistochemistry ( Araújo & Giorgio 2015) and mass spectrometry (Tei- xeira et al 2015) and a protective DNA vaccine encoding antigens and HSP70 genes ( Campbell et al 2003) have been characterised in L. amazonensis experimental models, little is known about the biological role of HSP70 in this parasite species. Here, the mitochondrial bioenergetics of L. amazonensis transfected with HSP70 were determined, and the rates of infection, the resistance to stress and the changes of the parasite’s morphology were evaluated using different stress conditions.…”

Hypoxia, Hypoxia-Inducible Factor-1α, and Innate Antileishmanial Immune Responses

“…Underscoring the potential important role of VEGF-A/VEGFR-2 signaling, Araújo and Giorgio suggest that VEGF-A levels upon infection might predict the outcome of L. amazonensis- infection. They recorded higher VEGF-A levels in healer mice compared to non-healer mice ( 34 ). Since VEGF-A is a known HIF-1α target ( 35 ) and HIF-1α is present in L. amazonensis- and L. major -infected lesions in humans and in preclinical models ( 26 , 33 , 34 , 36 ), it is possible that HIF-1α plays a role in infection-induced proliferation of the endothelial cells.…”