Molecular Regulation of Macrophage Class Switching in Indian Post-kala-azar Dermal Leishmaniasis (PKDL)
Mitali Chatterjee, Srija Moulik, Debkanya Dey, Debanjan Mukhopadhyay, Shibabrata Mukherjee and Susmita Roy
from: Molecular Biology of Kinetoplastid Parasites (Edited by: Hemanta K. Majumder). Caister Academic Press, U.K. (2018) Pages: 81-96.
Leishmania donovani, the causative parasite responsible for Visceral Leishmaniasis (VL) and its chronic dermal sequel, post-kala-azar dermal leishmaniasis (PKDL) manipulates host monocytes/macrophages for ensuring its survival. Information regarding macrophage polarization is primarily derived from murine models, but growing evidence is emphasizing the inadequacy of direct inter-species translation. Accordingly, the status of monocytes/macrophages with regard to plasticity and polarization in circulation and dermal lesions of patients with PKDL was characterized. The raised plasma levels of IL-4/IL-13 and IL-10 in patients with PKDL confirmed the presence of a microenvironment conducive for alternative activation of monocytes/macrophages. Furthermore, the mRNA expression of il-10, ifn-γ, mrc-1, arg-1,, vitamin D signalling pathway (vdr, cyp27b1, ll-37), was examined in circulation and lesional sites, wherein there was a consistent increase in expression of M2 markers. Conversely, the classical macrophage activation markers showed a consistent decline in generation of reactive oxygen and nitrogen intermediates, expression of Toll like receptors 2 and 4 (CD282/284) along with impairment of the MAP kinase pathway. Taken together, impairment of antigen presentation along with an increased presence of alternatively activated monocyte/macrophage subsets sustained parasite survival and facilitated disease persistence. Accordingly, immunomodulators capable of evoking a reduction in M2 monocytes/macrophage population or enhancing their switching from M2 to M1 could be an effective chemotherapeutic strategy against Leishmaniasis read more ...