Cathepsin G cleaves and activates IL-36γ and promotes the inflammation of psoriasis

Abstract

Background

IL-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.

Objectives

This study aims to investigate the activation of IL-36γ by cathepsin G (CG) and neutrophil elastase (NE).

Materials and methods

We 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.

Results

Purified 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.

Conclusion

CG 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.

Keywords:

• psoriasis
• IL-36
• neutrophil
• cathepsin
• elastase

Acknowledgments

This work was supported by the National Natural Science Foundation of China (81673062), the Youth Medical Talent of Empowering Medicine through Science and Education Program, and the Professionals from Six-Pronged Top-Talent Program (LGY2018052).

Disclosure

The authors report no conflicts of interest in this work.