Leishmania braziliensis Infection Enhances Toll-Like Receptors 2 and 4 Expression and Triggers TNF-α and IL-10 Production in Human Cutaneous Leishmaniasis.

Ludmila P Polari,Michael Macedo,Pedro Paulo Carneiro,Edgar M Carvalho,Phillip Scott,Paulo R L Machado,Olívia Bacellar

doi:10.3389/fcimb.2019.00120

Abstract

Cutaneous leishmaniasis (CL) caused by infection with Leishmania braziliensis is characterized by an exaggerated inflammatory response that controls the parasite burden, but also contributes to pathology. While myeloid cells are required to eliminate the parasite, recent studies indicate that they may also participate in the inflammatory response driving disease progression. The innate immune response to leishmania is driven in part by the Toll-like receptors (TLRs) TLR2, TLR4, and TLR9. In this study, we used flow cytometric analysis to compare TLR2 and TLR4 expression in monocyte subsets (classical, intermediate, and non-classical) from CL patients and healthy subjects (HS). We also determined if there was an association of either the pro-inflammatory cytokine TNF or the anti-inflammatory cytokine IL-10 with TLR2 or TLR4 expression levels after L. braziliensis infection. In vitro infection with L. braziliensis caused CL monocytes to up-regulate TLR2 and TLR4 expression. We also found that intermediate monocytes expressed the highest levels of TLR2 and TLR4 and that infected monocytes produced more TNF and IL-10 than uninfected monocytes. Finally, while classical and intermediate monocytes were mainly responsible for TNF production, classical monocytes were the main source of IL-10. Collectively, our studies revealed that up-regulated TLR2/4 expression and TNF production by intermediate/inflammatory subsets of monocytes from patients correlates with detrimental outcome of cutaneous leishmaniasis.

Highlights

The protozoan parasite leishmania is the causal agent of tegumentary and visceral leishmaniasis
The expression and CD14 CD16 was not modified after infection with L.braziliensis but it known that the frequency of intermediate monocytes is higher in Cutaneous leishmaniasis (CL) patients than in healthy subjects (HS) (Soares et al, 2006; Passos et al, 2015)
The Toll-like receptors (TLRs) are a well-characterized class of pattern recognition receptors that are expressed on phagocytes and interact with PAMPs expressed on the surface of infectious agents (Ozinsky et al, 2000)

Summary

Introduction

The protozoan parasite leishmania is the causal agent of tegumentary and visceral leishmaniasis. The immune response to L. braziliensis is characterized by a strong Th1 response with high production of IFN-γ, TNF and other proinflammatory cytokines (Bacellar et al, 2002; Gomes-Silva et al, 2007; Faria et al, 2012; Gonzalez-Lombana et al, 2013) This defense mechanism is important to control parasite growth and dissemination, but the exaggerated inflammation, mainly due the reduced ability of IL-10 to appropriately down regulate the immune response to leishmania antigens (Bacellar et al, 2002; Gonzalez-Lombana et al, 2013; Oliveira et al, 2014), contributes to the pathology of CL (Antonelli et al, 2005; Santos Cda et al, 2013; Cardoso et al, 2015; Novais et al, 2017). In L. braziliensis infection we have shown that macrophages from CL patients produce high amounts of TNF, CXCL9, CXCL10, and CCL3 after leishmania infection but their ability to kill the parasite is impaired (Giudice et al, 2012; Muniz et al, 2016)

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Results

Conclusion