"Autoinflammatory psoriasis"-genetics and biology of pustular psoriasis

Abstract

Psoriasis is a chronic inflammatory skin condition that has a fairly wide range of clinical presentations. Plaque psoriasis, which is the most common manifestation of psoriasis, is located on one end of the spectrum, dominated by adaptive immune responses, whereas the rarer pustular psoriasis lies on the opposite end, dominated by innate and autoinflammatory immune responses. In recent years, genetic studies have identified six genetic variants that predispose to pustular psoriasis, and these have highlighted the role of IL-36 cytokines as central to pustular psoriasis pathogenesis. In this review, we discuss the presentation and clinical subtypes of pustular psoriasis, contribution of genetic predisposing variants, critical role of the IL-36 family of cytokines in disease pathophysiology, and treatment perspectives for pustular psoriasis. We further outline the application of appropriate mouse models for the study of pustular psoriasis and address the outstanding questions and issues related to our understanding of the mechanisms involved in pustular psoriasis.

Keywords: Autoinflammation; Clinical features; Genetics; Histology; IL-36; Pustular psoriasis.

Fig. 1

Clinical presentations of pustular psoriasis. Clinical photographs of patients with pustular forms of psoriasis. The patient in (a) has a robust and acute inflammatory response in the skin with marked erythema, edema, and central pustulation, with very limited amount of scaling, characteristic of acute pustular psoriasis. The patient in (b) has annular and serpiginous lesions with pustules located on the periphery of the inflamed areas, characteristic of annular pustular psoriasis. The patient in (c) has resolving pustular psoriasis. Often, in these patients, the pustules have a “dried up” appearance with slight brown discoloration. The stratum corneum often peels off with a characteristic trailing scale. “Resolved” pustular lesions often transition into erythematous patches and plaques with fine superficial scaling. When generalized, this would be consistent with erythrodermic psoriasis, a clinical state that frequently follows widespread pustular psoriasis

Fig. 2

Histology of pustular psoriasis. H&E of (a) normal skin and skin from two generalized pustular psoriasis cases, one in the background of plaque psoriasis (b) and the other spontaneous (c). Thus, the section in (b) demonstrates neutrophil microabscesses in the stratum spinulosum and stratum corneum on a background of marked acanthosis and elongated rete ridges characteristic of plaque psoriasis. (c) Demonstrates a neutrophil-containing macroscopic pustule underneath the stratum corneum on a background of otherwise near normal skin

Fig. 3

IL-36 autocrine and autoinflammatory circuits. Keratinocytes are the major source of IL-36 in the skin. IL-36 expression can be induced by other pro-inflammatory cytokines, including IL-1, TNF, and IL-17A. IL-36 is secreted as full-length “pro-IL-36.” When exposed to neutrophil-derived proteases, including elastase, cathepsin G, or protease 3, IL-36 cytokines are enzymatically cleaved into a truncated form that has >500-fold greater biological activity. This truncated IL-36 can act back on keratinocytes via the IL-36 receptor (IL-36R) to induce even more IL-36 expression, amplifying the circuit, as well as expression of neutrophil chemokines such as CXCL1, CXCL2, CXCL6, and CXCL8 (IL-8) that attract progressively greater numbers of neutrophils into the skin. The serine protease inhibitors SERPINA1 and SERPINA3 can inhibit neutrophil proteases. Genes shown in red have been shown to genetically predispose to pustular forms of psoriasis

Fig. 4

IL-36 amplification circuit in pustular psoriasis. a Shows the role of the IL-36 autocrine circuit in amplifying inflammation in pustular psoriasis. IL-36 leads to the induction of a number of cytokines and chemokines that drive various aspects of psoriasis, such as neutrophil chemotaxis (CXCL1, CXCL2, CXCL6, CXCL8), Th17 chemotaxis (CCL20), antimicrobial responses (S100A7, S100A7A, DEFB4, LL-37), and pro-inflammatory cytokines (IL-7, IL-15, IL-17C, IL-19, IL-36). b demonstrates the induction of gene expression via RNA sequencing in human primary keratinocytes upon IL-36 stimulation for 24 h, which again includes genes important for neutrophil infiltration, antimicrobial responses, pro-inflammatory cytokines, and type I interferon responses (MX1, MX2, OASL)