Pathophysiology of generalized pustular psoriasis

Abstract

Psoriasis is a chronic, immune-mediated skin disease that affects over 3% of adults in the United States. Psoriasis can present in several clinical forms. Of these, generalized pustular psoriasis is an acute, severe form, associated with increased morbidity and mortality. Unlike the more common plaque psoriasis, which is thought to feature dysregulation of the adaptive immune system, generalized pustular psoriasis reflects heightened autoinflammatory responses. Recent advances in genetic and immunological studies highlight a key role of the IL-36 immune axis in the pathogenesis of generalized pustular psoriasis. In this article, we review the psoriatic subtypes and discuss diagnostic criteria of generalized pustular psoriasis, discuss several newly identified genetic variants associated with pustular disease in the skin, and discuss how these mutations shed light on pustular disease mechanisms. Furthermore, we gather insights from recent transcriptomic studies that similarly implicate a pathogenic role of the IL-36 immune axis in generalized pustular psoriasis.

Keywords: IL-36; autoinflammation; generalized pustular psoriasis; genetics; psoriasis vulgaris.

Figure 1:. Clinical psoriatic subtypes.

Clinically, psoriasis may be differentiated into non-pustular and pustular forms. Pustular psoriasis may be further stratified into localized forms or diffuse, widespread forms.

Figure 2:. IL-36 activation pathway.

IL-36 cytokines are secreted as low-activity precursors, pro-IL-36, which by the action of various proteases (cat G-cathepsin G; cat S-cathepsin S; elastase; proteinase-3) are cleaved into biologically active IL-36 agonists, IL-36α, IL-36β, and IL-36γ or antagonist IL-36Ra. IL-36 agonist processing increases their biologic activity by roughly 500-fold. IL-36 agonists form a binary complex with IL-36R, which recruits the IL-1 receptor accessory protein (IL-1RAcP) coreceptor. The ternary complex then binds to myeloid differentiated protein 88 (MyD88) to activate nuclear transcription factor kappa B (NF-kB) and mitogen-activated protein kinase (MAPK) signaling pathways and regulate downstream transcription of target genes and generate inflammatory responses. This pathway may be antagonized by IL-36Ra or IL-38. Alternatively, protease inhibition by SERPINA1 or SERPINA3 can prevent the generation of IL-36 agonists.

Figure 3:. The IL-36 autoinflammatory circuit.

IL-36 is highly expressed in skin keratinocytes, and IL36 expression can be enhanced by inflammatory cytokines from other immune cells (eg. DC-dendritic cells; CD4⁺ T cells), IL-1, TNFα, and IL-17A. IL-36 is secreted as an inactive precursor, pro-IL-36, which is cleaved and activated by proteases, cathepsin S, cathepsin G, elastase, and proteinase-3. The activation process may be enhanced by neutrophil extracellular traps (NETs). Activated IL-36 can interact with the IL-36 receptor to further promote IL36 expression and expression of neutrophil chemokines, CXCL1, CXCL2, and CXCL8, resulting in increased neutrophil (PMN) recruitment to the skin. Additionally, IL36 binding promotes downstream nuclear-factor kappa b (NF-kB) and mitogen-activated protein kinase (MAPK) signaling pathways. Negative regulators of the circuit include serine protease inhibitors, SERPINA1 and SERPINA3, which inhibit protease activity. Molecules harboring GPP-associated mutations that inhibit this circuit under normal conditions can be found in the red circles: IL-36Ra, SERPINA1, SERPINA3, MPO, and TNIP, and those harboring mutations in genes that promote the circuit are in the green circle: CARD14.

Figure 4:. Transcriptomic investigations reveal that generalized pustular psoriasis is an autoinflammatory disease.

Genes enriched in generalized pustular psoriasis were more consistent with those involved in innate immunity. This contrasted with the overexpression of genes involved in acquired immunity in psoriasis vulgaris. The figure was adapted from Johnston et al.