IL-1β production by intermediate monocytes is associated with immunopathology in cutaneous leishmaniasis

Abstract

Cutaneous leishmaniasis due to Leishmania braziliensis infection is an inflammatory disease which skin ulcer development is associated with mononuclear cells infiltrate and high levels of inflammatory cytokines production. Recently, NOD-like receptor family, pyrin domain containing 3 (NLRP3) inflammasome activation and IL-1β production has been associated with increased pathology in murine cutaneous leishmaniasis. We hypothesized that cutaneous leishmaniasis patients have increased expression of NLRP3 leading to high levels of IL-1β production. In this work we show high production of IL-1β in biopsies and Leishmania antigen-stimulated peripheral blood mononuclear cells (PBMC) from patients infected with L. braziliensis, and reduced IL-1β levels after cure. IL-1β production positively correlated with the area of necrosis in lesions and duration of the lesions. The main source of IL-1β was intermediate monocytes (CD14++CD16+). Furthermore, our murine experiments show that IL-1β production in response to L. braziliensis was dependent on NLRP3, Caspase-1 and caspase-recruiting domain (ASC). Additionally, we observed an increased expression of NLRP3 gene in macrophages and NLRP3 protein in intermediate monocytes from cutaneous leishmaniasis patients. These results identify an important role for human intermediate monocytes for the production of IL-1β which contributes to the immunopathology observed in cutaneous leishmanisis patients.