Aryl Hydrocarbon Receptor-Signaling Regulates Early Leishmania major-Induced Cytokine Expression

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.

Going ballistic: Leishmania nuclear subversion of host cell plasticity

“…Our recent transcriptomic analyses revealed profound changes in TF expression levels in L. amazonensis-infected DCs [27] and BMDMs [26] (Figure 4A), including (i) suppression of various proinflammatory NF-κB family members, (ii) induction of the activating transcription factor 3 (ATF3) that negatively regulates inflammatory cytokine gene expression [32], and (iii) reduced expression of the aryl hydrocarbon receptor (AhR) (Figure 4A), a TF linked to macrophage polarization and production of tumor necrosis factor (TNF) and nitric oxide synthase (NOS) in Leishmania major-infected macrophages [33]. These examples uncover a recursive regulatory network where the TF landscape itself is under transcriptional control, which may involve different levels of epigenetic regulation.…”

Epithelial cell invasion by salmonella typhimurium induces modulation of genes controlled by aryl hydrocarbon receptor signaling and involved in extracellular matrix biogenesis

“…In this context, the role of AhR in response to pathogens is an emerging theme. Its involvement in viral [ 61 , 62 ], bacterial [ 63 , 64 ] and parasitic infections [ 65 , 66 ] has been documented. Bessede et al [ 67 ].…”

Transcriptional signatures in human macrophage-like cells infected by Leishmania infantum, Leishmania major and Leishmania tropica

“…At 24h post-infection, the results of pathway enrichment analysis with the upregulated multiple gene list, (Fig 4A ) evidenced that pathways enriched only in L. infantum-infected cells included: VEGFA-VEGFR2 signaling pathway, NFE2L2 regulating anti-oxidant/detoxification enzymes, IL17 signaling (including TNF signaling, IL18 signaling and Interleukin-4 and Interleukin-13 signaling). Moreover, Nuclear receptors meta-pathway and Fluid shear stress and atherosclerosis (comprising Aryl hydrocarbon receptor pathway, that mediates inflammation and production of TNF in the context of Leishmania infection) [60] were also included.…”