Th17 micro-milieu regulates NLRP1-dependent caspase-5 activity in skin autoinflammation

Abstract

IL-1β is a potent player in cutaneous inflammation and central for the development of a Th17 micro-milieu in autoinflammatory diseases including psoriasis. Its production is controlled at the transcriptional level and by subsequent posttranslational processing via inflammatory caspases. In this study, we detected inflammatory caspase-5 active in epidermal keratinocytes and in psoriatic skin lesions. Further, interferon-γ and interleukin-17A synergistically induced caspase-5 expression in cultured keratinocytes, which was dependent on the antimicrobial peptide psoriasin (S100A7). However, diseases-relevant triggers for caspase-5 activity and IL-1β production remain unknown. Recently, extranuclear DNA has been identified as danger-signals abundant in the psoriatic epidermis. Here, we could demonstrate that cytosolic double-stranded (ds) DNA transfected into keratinocytes triggered the activation of caspase-5 and the release of IL-1β. Further, interleukin-17A promoted caspase-5 function via facilitation of the NLRP1-inflammasome. Anti-inflammatory vitamin D interfered with the IL-1β release and suppressed caspase-5 in keratinocytes and in psoriatic skin lesions. Our data link the disease-intrinsic danger signals psoriasin (S100A7) and dsDNA for NLPR1-dependent caspase-5 activity in psoriasis providing potential therapeutic targets in Th17-mediated skin autoinflammation.

Caspase 1/11 Deficiency or Pharmacological Inhibition Mitigates Psoriasis-Like Phenotype in Mice

“…Although it was previously shown that the cleaved form of caspase 5 is present in lesional skin biopsy samples from psoriasis patients (Zwicker et al, 2017), we confirmed in a large number of lesional and nonlesional skin biopsy samples that cleaved forms of caspases 1, 4, and 5 are found in all lesional samples of tested psoriasis patients, whereas no cleaved forms are found in healthy donor samples. Moreover, cleaved forms of proinflammatory caspases were associated with an increase in the NLRP-3 and AIM-2 inflammasomes.…”

“…In our study, we showed that keratinocytes cultured in conditions mimicking psoriasis (TNF-a þ IL-17A) are primed to secrete IL-1b in an inflammasome-dependent manner. Recently, it has been shown that the stimulation of keratinocytes with TNF-a alone or with IL-17A alone did not trigger caspase activation (Zwicker et al, 2017) but that the combination of at least two proinflammatory cytokines is necessary (Cho et al, 2012), suggesting that in the presence of several proinflammatory cytokines (IFN-g, TNF-a, IL-17, and IL-22), a strong increase in proinflammatory caspases could be obtained. This hypothesis is in agreement with what happens in psoriatic skin, where keratinocytes are in direct contact with a huge amount of proinflammatory cytokines secreted from the recruited immune cells and from themselves.…”

“…Although increased mRNA expression of proinflammatory caspases 1, 4, and 5 in lesional biopsy samples from psoriasis patients has been already observed (Salskov-Iversen et al, 2011;Zwicker et al, 2017) and expression of cleaved caspase 5 could be detected in one psoriasis patient (Zwicker et al, 2017), we decided to assess the expression of caspases to confirm their activation status in a large cohort of psoriasis patients. We performed Western blot analysis of skin extracts from nonlesional and lesional biopsy samples.…”

“…It has been showed that activated caspase 1 is increased in lesional skin samples from psoriasis patients compared with nonlesional samples (Johansen et al, 2007;Marchetti et al, 2009). Moreover, an increase in the mRNA expression of caspase 5 was found in lesional biopsy samples (Salskov-Iversen et al, 2011), and a constitutive expression of this caspase was observed in the epidermis of normal skin (Zwicker et al, 2017). However, the contribution of inflammatory caspases in psoriasis pathogenesis is controversial, because Cho et al (2012) reported a decrease in the epidermal thickness associated with a significant reduction in IL-1b levels in caspase 1 e/e mice treated with imiquimod (IMQ) (Cho et al, 2012), whereas another recent study concluded that the invalidation of caspase 1 had no impact on reducing the psoriasis-like phenotype after IMQ treatment (Rabeony et al, 2015).…”

Further progress for therapeutic solutions in psoriasis

“…The current understanding of psoriasis pathogenesis involves dynamic networks of interrelated cells (immune cells, keratinocytes, peripheral nerves), receptors (TLRs, TRPV1, NaV 1.8) and molecules (chemokines, cytokines, proinflammatory mediators or even ds DNAs). Accelerated epidermopoiesis is the biological outcome of this pathological process.…”