Hif-1alpha induced expression of Il-1beta protects against mycobacterial infection in zebrafish

Abstract

Drug resistant mycobacteria are a rising problem worldwide. There is an urgent need to understand the immune response to TB to identify host targets that, if targeted therapeutically, could be used to tackle these currently untreatable infections. Here, we use an Il-1β fluorescent transgenic line to show that there is an early innate immune pro-inflammatory response to well-established zebrafish models of inflammation and Mycobacterium marinum (Mm) infection. We demonstrate that host-derived hypoxia signalling, mediated by the Hif-1α transcription factor, can prime macrophages with increased levels of Il-1β in the absence of infection, upregulating neutrophil antimicrobial nitric oxide production, leading to greater protection against infection. Our data link Hif-1α to proinflammatory macrophage Il-1β transcription in vivo during early mycobacterial infection and importantly highlight a host protective mechanism, via antimicrobial nitric oxide, that decreases disease outcomes and that could be targeted therapeutically to stimulate the innate immune response to better deal with infections.

Dynamic control of proinflammatory cytokines Il-1β and Tnf-α by macrophages is necessary for functional spinal cord regeneration in zebrafish

“…Analysing touch-evoked swimming capacity, we found that wildtype animals swam distances that were comparable to those of unlesioned controls at 2 dpl, as previously described 1 . In contrast, recovery in irf8 larvae plateaued at 2 dpl and did not reach swim distances of unlesioned animals to at least 5 dpl (Fig.…”

“…To determine the mechanism of action for macrophages, we tested for possible interactions with a previously reported regeneration-promoting mechanism, comprising Wnt-dependent deposition of Col XII in the lesion site by pdgfrb:GFP + fibroblast-like cells 1 . General inhibition of the immune response with dexamethasone did not inhibit appearance of pdgfrb:GFP + fibroblast-like cells in the lesion site ( Fig.…”

“…At the same time, the larval system presents complex tissue interactions that allow us to better understand how axons can cross a non-neural lesion environment. For example, axons encounter Pdgfrb + fibroblast-like cells that deposit regenerationpromoting Col XII in the lesion site in a Wnt-signalling dependent manner 1 . These cellular and molecular components are present also in the injury sites of adult zebrafish and mammals 1 .…”

“…For example, axons encounter Pdgfrb + fibroblast-like cells that deposit regenerationpromoting Col XII in the lesion site in a Wnt-signalling dependent manner 1 . These cellular and molecular components are present also in the injury sites of adult zebrafish and mammals 1 . How cells of the immune system contribute to this growthconducive lesion site environment in zebrafish is unclear.…”

“…Zebrafish, in contrast to mammals, are capable of functional spinal cord regeneration after injury. Recovery of swimming function critically depends on regeneration of axonal connections across the complex non-neural injury site 1,2 . It is therefore important to determine the factors that allow axons to cross the lesion site in zebrafish.…”