2. Academic Validation
  3. Casting NETs on Psoriasis: The modulation of inflammatory feedback targeting IL-36/IL-36R axis

Casting NETs on Psoriasis: The modulation of inflammatory feedback targeting IL-36/IL-36R axis

  • Int Immunopharmacol. 2024 Dec 5;142(Pt B):113190. doi: 10.1016/j.intimp.2024.113190.
Zhi-Hong Zhang 1,  Zi-Ying Zhan 1,  Min Jiang 2,  Xiang-Yuan Wang 1,  Shu-Lin Quan 1,  Yan-Ling Wu 1,  Ji-Xing Nan 3,  Li-Hua Lian 4
Affiliations

Affiliations

  • 1 Key Laboratory of Traditional Chinese Korean Medicine Research of State Ethnic Affairs Commission, College of Pharmacy, Yanbian University, Yanji, Jilin Province 133002, China; Key Laboratory of Natural Medicines of the Changbai Mountain, Ministry of Education, College of Pharmacy, Yanbian University, Yanji, Jilin Province 133002, China.
  • 2 Department of Pharmacology, Binzhou Medical University, Yantai Campus, Yantai, Shandong Province, China.
  • 3 Key Laboratory of Traditional Chinese Korean Medicine Research of State Ethnic Affairs Commission, College of Pharmacy, Yanbian University, Yanji, Jilin Province 133002, China; Key Laboratory of Natural Medicines of the Changbai Mountain, Ministry of Education, College of Pharmacy, Yanbian University, Yanji, Jilin Province 133002, China. Electronic address: jxnan@ybu.edu.cn.
  • 4 Key Laboratory of Traditional Chinese Korean Medicine Research of State Ethnic Affairs Commission, College of Pharmacy, Yanbian University, Yanji, Jilin Province 133002, China; Key Laboratory of Natural Medicines of the Changbai Mountain, Ministry of Education, College of Pharmacy, Yanbian University, Yanji, Jilin Province 133002, China. Electronic address: lhlian@ybu.edu.cn.
PMID: 39306890 DOI: 10.1016/j.intimp.2024.113190
Abstract

NETosis happens when neutrophils are activated and neutrophil extracellular traps (NETs) are formed synchronously, which is a hallmark of psoriasis. However, the specific trigger that drives NET formation and the distinct contents and interaction with interleukin-36 receptor (IL-36R) of NETs remain to be further elucidated. This work identified NET formation driven by Toll-like Receptor (TLR) 3 ligand (especially polyinosinic-polycytidylic acid (Poly(I:C)) were enhanced by purinergic receptor P2X ligand-gated ion channel 7 receptor (P2X7R) ligands (especially adenosine 5'-triphosphate (ATP)). NET formation was accompanied by the secretion of inflammatory cytokines and characterized by IL-1β decoration. NET formation blockade decreased expressions of inflammatory cytokines and chemokines, which consequently improved inflammatory responses. Additionally, imiquimod (IMQ)-induced psoriasiform symptoms including neutrophilic infiltration tended to be time-sensitive. Mouse primary keratinocytes and mice deficient in Il1rl2, which encodes IL-36R, mitigated inflammatory responses and NET formation, thereby delaying the pathophysiology of psoriasis. Together, the findings provided the therapeutic potential for IL-36 targeting NET inhibitors in psoriasis treatment.

Keywords

IL-36R; NETosis; Neutrophil extracellular traps; Psoriasis.

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