Immunological role of keratinocytes in leishmaniasis

Abstract

Following inoculation of Leishmania, a protozoan parasite, into the skin of a mammal, the epidermal keratinocytes recognize the parasite and influence the local immune response that can give rise to different outcomes of leishmaniasis. The early keratinocyte‐derived cytokines and keratinocytes‐T cells interactions shape the anti‐leishmanial immune responses that contribute to the resistance or susceptibility to leishmaniasis. The keratinocyte‐derived cytokines can directly potentiate the leishmanicidal activity of monocytes and macrophages. As keratinocytes express MHC‐II and enhance the expression of costimulatory molecules, these cells act as antigen‐presenting cells (APCs) in cutaneous leishmaniasis (CL). Depending on the epidermal microenvironment, the keratinocytes induce various types of effector CD4+ T cells. Keratinocyte apoptosis and necrosis have been also implicated in ulceration in CL. Further, keratinocytes contribute to the healing of Leishmania‐related cutaneous wounds. However, keratinocyte‐derived IL‐10 may play a key role in the development of post‐kala‐azar dermal leishmaniasis (PKDL). In this review, a comprehensive discussion regarding the multiple roles played by keratinocytes during leishmaniasis was provided, while highlighting novel insights concerning the immunological and pathological roles of these cells.

Bidirectional cytokine-microRNA control: A novel immunoregulatory framework in leishmaniasis

“…major while attenuating the responses against L . donovani [ 8 , 32 ]. miR-3620 and miR-6385 are highly elevated in L .…”

“…However, the exact mechanism of PS-miRNA-6540 interaction awaits elucidation. Once inside, the parasite proliferates causing a hypoxic condition that induces hypoxia-inducible factor-1α (HIF-1α) expression potentiating macrophage-mediated immunity against L. amazonensis and L. major while attenuating the responses against L. donovani [8,32]. miR-3620 and miR-6385 are highly elevated in L. donovani infected macrophages, which probably down-regulate hypoxia-induced genes [22].…”

“…IL-10-induced immunosuppression plays a prominent role in PKDL development [8]. The L. donovani isolates from VL patients induce more IL-10 in macrophages than the L. donovani isolates from PKDL patients perhaps due to differential expression of miRNAs [26].…”

“…IFN-γ and TNF-α from Th1 cells activate macrophages to induce NO and ROS eliminating Leishmania , while IL-4, IL-10, and TGF-β from Th2 and Treg cells inhibit the leishmanicidal functions of macrophages [ 6 , 7 ]. Macrophage-derived IL-10 and TGF-β exert preventive effects on the M1 macrophages and Th1 cells while promoting Th2/Treg cell differentiation [ 8 , 9 ]. A basic macrophage—T-cell network is shown in Fig 1 .…”

“…IFN-γ and TNF-α from Th1 cells activate macrophages to induce NO and ROS eliminating Leishmania, while IL-4, IL-10, and TGF-β from Th2 and Treg cells inhibit the leishmanicidal functions of macrophages [6,7]. Macrophagederived IL-10 and TGF-β exert preventive effects on the M1 macrophages and Th1 cells while promoting Th2/Treg cell differentiation [8,9]. A basic macrophage-T-cell network is shown in Fig 1. In this intriguing battle between the host and the parasite, Leishmania the parasite enters the host macrophages and subverts its defense mechanisms-phagosomal maturation, MHC class-I and -II-mediated antigen presentation, inflammatory cytokine productions, activation of leishmanicidal mechanisms such as generation of reactive oxygen species (ROS), and nitric oxide (NO)-and multiply within phagolysosomes [10][11][12].…”