Date Published: October 23, 2015
Publisher: Public Library of Science
Author(s): Debanjan Mukhopadhyay, Shibabrata Mukherjee, Susmita Roy, Jane E. Dalton, Sunanda Kundu, Avijit Sarkar, Nilay K. Das, Paul M. Kaye, Mitali Chatterjee, Diane McMahon-Pratt. http://doi.org/10.1371/journal.pntd.0004145
Abstract: AbstractThe 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.
Partial Text: 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). Post kala-azar dermal leishmaniasis (PKDL) is the dermal sequel of VL, wherein Leishmania parasites remain restricted to the skin and manifest as nodular, papular, hypopigmented macular lesions, erythematous plaques and/or a mixed phenotype, termed as polymorphic . The etiopathogenesis of PKDL is still unclear and a consensus is yet to emerge regarding possible causes for the generally viscerotropic L. donovani parasite to generate PKDL. In PKDL, similar to other leishmaniasis, Leishmania have developed several strategies to outmanoeuvre host immunity via subverting and/or suppressing macrophage microbicidal activities .
Papulo-nodules in PKDL being parasite-rich have fuelled speculation of its pivotal role in the transmission of VL especially in South Asia, where VL is anthroponotic making patients with PKDL the strongest contenders to be the disease reservoir. Accordingly, its eradication should be an essential component of the VL elimination programme [http://www.who.int/tdr/publications/documents/kala_azar_indicators.pdf; last accessed on 1st March 2015], emphasising the importance of establishing a greater understanding of the immunopathogenesis of PKDL. In the absence of an experimental model, the challenge of delineating the immunoclinical determinants of PKDL lies squarely on the shoulders of clinical researchers which constituted the focus of this study (Fig 1).