Abstract
Prominent skin involvement is a defining characteristic of autoinflammatory disorders caused by abnormal IL-1 signaling. However, the pathways and cell types that drive cutaneous autoinflammatory features remain poorly understood. We sought to address this issue by investigating the pathogenesis of pustular psoriasis, a model of autoinflammatory disorders with predominant cutaneous manifestations. We specifically characterized the impact of mutations affecting AP1S3, a disease gene previously identified by our group and validated here in a newly ascertained patient resource. We first showed that AP1S3 expression is distinctively elevated in keratinocytes. Because AP1S3 encodes a protein implicated in autophagosome formation, we next investigated the effects of gene silencing on this pathway. We found that AP1S3 knockout disrupts keratinocyte autophagy, causing abnormal accumulation of p62, an adaptor protein mediating NF-κB activation. We showed that as a consequence, AP1S3-deficient cells up-regulate IL-1 signaling and overexpress IL-36α, a cytokine that is emerging as an important mediator of skin inflammation. These abnormal immune profiles were recapitulated by pharmacological inhibition of autophagy and verified in patient keratinocytes, where they were reversed by IL-36 blockade. These findings show that keratinocytes play a key role in skin autoinflammation and identify autophagy modulation of IL-36 signaling as a therapeutic target.
Highlights
Autoinflammatory disorders (AIDs) are a group of inherited conditions caused by abnormal activation of the innate immune system
Validation of AP1S3 as a pustular psoriasis gene we previously reported that two AP1S3 mutations (p.Phe4Cys and p.Arg33Trp) account for approximately 10% of European pustular psoriasis patients (Setta-Kaffetzi et al, 2014), the rarity of the disease has hindered the replication of this finding
We investigated the pathogenesis of pustular psoriasis, focusing our attention on AP1S3, a gene that is mutated in this disease
Summary
Autoinflammatory disorders (AIDs) are a group of inherited conditions caused by abnormal activation of the innate immune system. AIDs typically present with recurrent and seemingly unprovoked episodes of systemic upset, which are almost invariably accompanied by joint and skin inflammation (Aksentijevich and Kastner, 2011). The latter can manifest with urticarial, pustular, or ulcerative eruptions, which are considered important markers of disease activity (Beer et al, 2014).
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