<p>Cathepsin G cleaves and activates IL-36&gamma; and promotes the inflammation of psoriasis</p>

Abstract

BackgroundIL-36γ is considered to be a valuable biomarker in psoriatic patients, which is expressed as an inactive precursor that needs to be proteolytically processed and activated, and neutrophil-derived proteases seemed to be potent activating enzymes of IL-36γ.ObjectivesThis study aims to investigate the activation of IL-36γ by cathepsin G (CG) and neutrophil elastase (NE).Materials and methodsWe used inactive recombinant full-length (FL)-IL-36γ with different doses of NE or CG to stimulate HaCaT cells; neutrophil extracellular traps (NETs) were prepared to act on FL-IL-36γ and then stimulate HaCaT cells. Real-time quantitative PCR and ELISA were performed to detect CXCL-1 and CXCL-8 expression. We developed imiquimod-induced psoriasis-like mouse model to evaluate the effect of hypodermic injection of neutrophil-derived protease or its inhibitor. Histopathology and Western blotting were conducted for effect assessment.ResultsPurified CG cleaved and activated recombinant human FL-IL-36γ to promote CXCL-1 and CXCL-8 expression by human keratinocytes, and NETs activated FL-IL-36γ and the activation was inhibited by serpin A3. CG induced expression of a more truncated IL-36γ in psoriasiform lesion of mice and aggravated the psoriasis-like lesion induced by imiquimod, whereas recombinant serpin A3 alleviated the severity of the psoriasis-like mouse mode.ConclusionCG has the ability to cleave and activate IL-36γ and aggravate imiquimod-induced mouse psoriasiform lesion. Thus, CG-specific inhibitors might be promising therapeutic drugs for psoriasis.

Neutrophils in Psoriasis

“…MPO is involved in the respiratory burst and can bind to CD11b/CD18 integrins, thereby contributing to the upregulation and augmentation of neutrophil degranulation in psoriasis (86). Furthermore, the neutrophil granule-derived serine proteinases, such as NE, proteinase 3, and cathepsin G, can activate interleukin (IL)-36 cytokine and lead to the escalation of local psoriatic tissue inflammation (87, 88). Proteinase 3 cleaves and converts the resting TNFα located in membrane of epithelial cells (mTNFα) to an activated state called soluble TNFα (sTNFα), which participates in the psoriasis complex inflammatory reactions (Figure 2).…”

The Significance of IL-36 Hyperactivation and IL-36R Targeting in Psoriasis

“…IL-36 cytokines, such as all the IL-1 family members except for IL-1Ra, are synthesized without a signal peptide and therefore are not secreted via the endoplasmic reticulum-Golgi pathway and the mechanism of their release remains yet undefined [31]. Post-translational processing is required for full agonist or antagonist activity of all IL-36 members [5,32]. Similarly, recent in vitro and in vivo studies demonstrated that N-terminally truncated fragments of IL-38 (20–152 and 7–152 amino acid fragments) have increased biological activity compared to full-length form [33,34].…”

“…Similarly, recent in vitro and in vivo studies demonstrated that N-terminally truncated fragments of IL-38 (20–152 and 7–152 amino acid fragments) have increased biological activity compared to full-length form [33,34]. Neutrophil-derived proteases seem to be responsible for IL-36 agonists maturation [32,35]. However, it is unclear whether truncation of IL-36 agonists and antagonists occurs in humans under pathologic conditions.…”

“…However, in addition to IL-36R, IL-38 can bind, albeit with low affinity, to IL-1R1, but also to the orphan receptor Three Immunoglobulin Domain-containing IL-1 receptor-related 2 (TIGIRR-2), formerly known as interleukin 1 receptor accessory protein- like 1 (IL-1RAPL1) [32] (Figure 2). Mora et al recently demonstrated that IL-38 released by apoptotic cells inhibits the IL1RAPL1-dependent phosphorylation of JNK/AP1 cascade, thus limiting the production and release of inflammatory cytokines from human macrophages [33].…”

IL-36, IL-37, and IL-38 Cytokines in Skin and Joint Inflammation: A Comprehensive Review of Their Therapeutic Potential

“…IL-36α seems to be activated by both NE and cathepsin-G, however, with differential patterns. Conversely, whereas cathepsin-G and proteinase-3 preferentially activate IL-36β, IL-36γ can be processed by NE, proteinase-3, cathepsin-G [12], and cathepsin-S [13], the last being particularly important for enabling the IL-36γ-related inflammation in skin psoriasis [14]. Neutrophil extracellular traps (NETs), in addition to their antimicrobial role, can also serve as a platform for the activation of IL-1α and IL-36 cytokines through NETs-associated cathepsin-G and NE [15].…”