Abstract
Topical application of Aldara cream, containing the Toll-like receptor 7/8 agonist Imiquimod, is a widely used mouse model for investigating the pathogenesis of psoriasis. We have previously used this model to study the effects of peripheral inflammation on the brain, and reported a brain-specific response characterised by increased transcription, infiltration of immune cells and anhedonic-like behavior. Here, we perform a more robust characterisation of the systemic response to Aldara application and find a potent but transient response in the periphery, followed by a prolonged response in the brain. Mass spectrometry analysis of plasma and brain samples identified significant levels of Imiquimod in both compartments at molar concentrations likely to evoke a biological response. Indeed, the association of Imiquimod with the brain correlated with increased Iba1 and GFAP staining, indicative of microglia and astrocyte reactivity. These results highlight the potency of this model and raise the question of how useful it is for interpreting the systemic response in psoriasis-like skin inflammation. In addition, the potential impact on the brain should be considered with regards to human use and may explain why fatigue, headaches and nervousness have been reported as side effects following prolonged Aldara use.
Highlights
In addition to the local skin response, topical Aldara application was noted to cause systemic pro-inflammatory cytokine production and enlarged spleen and draining lymph nodes[4,6]
Having previously shown that topical Aldara treatment induces a transcriptional response in the brain that peaks 3–5 days after treatment, we sought to determine the temporal mechanisms of the brain response
We have shown that topical Aldara treatment induces a potent chemokine and cytokine response throughout the peripheral tissues and in the brain, and that these responses are temporally distinct
Summary
In addition to the local skin response, topical Aldara application was noted to cause systemic pro-inflammatory cytokine production and enlarged spleen and draining lymph nodes[4,6]. As well as its use for studying psoriasis-like inflammation in the local tissue, the Aldara model has been used to investigate the systemic effects of psoriatic inflammation. We have previously used the Aldara model to investigate the systemic effects of IMQ and TLR7 activation, with a particular focus on the distal brain response[6,9]. Whilst the PBL response was investigated alongside the brain as an indicator of systemic inflammation, the extent of the response was difficult to assess as we did not characterise a range of peripheral tissues or early time-points. The aim of this study was to systematically characterise the tissue response to Aldara treatment across a detailed time-course model to determine the most likely mechanism driving systemic inflammation. Our findings, presented in this current study, show IMQ is present in both the plasma and brain as early as 4 hours after treatment, suggesting the primary mechanism of immune activation of topical Aldara treatment is through the direct ligation of IMQ with TLR7 receptors throughout the body
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