Abstract
The early inflammatory skin micromilieu affects resistance in experimental infection with Leishmania major. We pursue the concept that macrophages, which take up parasites during early infection, exert decisive influence on the inflammatory micromilieu after infection. In order to analyze their distinctive potential, we identified differentially regulated genes of murine granuloma macrophages (GMΦ) from resistant and susceptible mice after their infection with metacyclic Leishmania major. We found induction of several cytokines in GMΦ from both strains and a stronger upregulation of the transcription factor aryl hydrocarbon receptor (AhR) in GMΦ from resistant mice. Using both an AhR agonist and antagonist we demonstrated that AhR is involved in Leishmania-induced production of TNF in macrophages. In vivo, single local injection of an AhR agonist in early lesions of susceptible mice caused an increased induction of Tnf and other cytokines in the skin. Importantly, local agonist treatment led to a reduction of disease severity, reduced parasite loads and a weaker Th2 response. Our results demonstrate that local activation of AhR has a beneficial effect in experimental leishmaniasis.
Highlights
Interaction of pathogens and innate immune cells is a crucial early event in infection
To identify genes that are regulated during infection of macrophages with L. major, granuloma macrophages (GM) from C57BL/6 and BALB/c mice where incubated with metacyclic L. major for 4 h with a multiplicity of infection (MOI) of 5:1
Because aryl hydrocarbon receptor (AhR) has recently been identified as an important regulator of innate immunity [22, 26, 32,33,34] and was implicated in regulation of resistance to experimental leishmaniasis [24, 35, 36], we focused on AhR
Summary
Interaction of pathogens and innate immune cells is a crucial early event in infection. We have identified several differentially regulated cytokines expressed in infected skin from resistant and susceptible mice early during infection. We identified differentially regulated genes between infected GM from BALB/c and C57BL/6 mice Among those we found transcription factor aryl hydrocarbon receptor (AhR), an inductor of xenobiotic compound-degrading enzymes, deserving a closer look because of its expanding role in immunity, especially macrophage function [22,23,24,25,26]. Peritoneal macrophages from Ahr knockout mice showed reduced NO production, but enhanced secretion of several cytokines like TNF and IL12 when polarized to a M1 subtype and stimulated with LPS [26]. As AhR is a transcriptional regulator implicated in resistance against Leishmania both in vitro in macrophages and in vivo, we chose to further analyze the role of AhR in early events determining resistance against L. major
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
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 call
