Abstract
The high level of functional diversity and plasticity in monocytes/macrophages has been defined within in vitro systems as M1 (classically activated), M2 (alternatively activated) and deactivated macrophages, of which the latter two subtypes are associated with suppression of cell mediated immunity, that confers susceptibility to intracellular infection. Although the Leishmania parasite modulates macrophage functions to ensure its survival, what remains an unanswered yet pertinent question is whether these macrophages are deactivated or alternatively activated. This study aimed to characterize the functional plasticity and polarization of monocytes/macrophages and delineate their importance in the immunopathogenesis of Post kala-azar dermal leishmaniasis (PKDL), a chronic dermatosis of human leishmaniasis. Monocytes from PKDL patients showed a decreased expression of TLR-2/4, along with an attenuated generation of reactive oxidative/nitrosative species. At disease presentation, an increased mRNA expression of classical M2 markers CD206, ARG1 and PPARG in monocytes and lesional macrophages indicated M2 polarization of macrophages which was corroborated by increased expression of CD206 and arginase-1. Furthermore, altered vitamin D signaling was a key feature in PKDL, as disease presentation was associated with raised plasma levels of monohydroxylated vitamin D3 and vitamin D3- associated genes, features of M2 polarization. Taken together, in PKDL, monocyte/macrophage subsets appear to be alternatively activated, a phenotype that might sustain disease chronicity. Importantly, repolarization of these monocytes to M1 by antileishmanial drugs suggests that switching from M2 to M1 phenotype might represent a therapeutic opportunity, worthy of future pharmacological consideration.
Highlights
Leishmaniases comprise a group of heterogeneous parasitic diseases caused by the protozoan parasite Leishmania with its spectrum ranging from a self-healing cutaneous variant to the often fatal visceral leishmaniasis (VL)
Monocyte/macrophage subsets following their polarization by the microenvironement serve as important immune sentinels that play a vital role in host defense and homeostasis
The polarization of macrophage function has been broadly classified as M1 and M2 activation, wherein M1 polarised cells display a strong pro-inflammatory microbicidal response, while M2 polarization is linked to production of an anti-inflammatory milieu leading to tissue regeneration and wound healing
Summary
Leishmaniases comprise a group of heterogeneous parasitic diseases caused by the protozoan parasite Leishmania with its spectrum ranging from a self-healing cutaneous variant to the often fatal visceral leishmaniasis (VL). In PKDL, similar to other leishmaniasis, Leishmania have developed several strategies to outmanoeuvre host immunity via subverting and/or suppressing macrophage microbicidal activities [2]. It is universally accepted that monocytes-macrophages have a range of biological roles being inducers, regulators and effectors of innate and acquired immunity. They actively participate in physiological processes associated with wound healing and tissue repair [3]. This study validated that inhibition of arginase-1 or ornithine decarboxylase abrogated parasite replication within human macrophages [10]
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
