Intestinal guard: Human CXCL17 modulates protective response against mycotoxins and CXCL17-mimetic peptides development

• Published in: Biochemical pharmacology Vol. 188; p. 114586
• Main Authors: Sun, Chongjun, Shen, Haokun, Cai, Haiming, Zhao, Zengjue, Gan, Guanhua, Feng, Saixiang, Chu, Pinpin, Zeng, Min, Deng, Jinbo, Ming, Feiping, Ma, Miaopeng, Jia, Junhao, He, Rongxiao, Cao, Ding, Chen, Zhiyang, Li, Jiayi, Zhang, Linghua
• Format: Journal Article
• Language: English
• Published: England Elsevier Inc 01-06-2021
• Subjects: Apoptosis; CXCL17; Inflammation; Mimetic peptides; Mycotoxin; CXCL17; Inflammation; Mimetic peptides; Mycotoxin; Apoptosis
• ISSN: 0006-2952; 1873-2968
• DOI: 10.1016/j.bcp.2021.114586

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•CXCL17 intense production induced by mycotoxins is ROS-dependent via p38 and JNK.•CXCL17 ameliorates mycotoxin-induced inflammation and apoptosis by the PI3K/AKT/mTOR.•Effective analogs CX1 and CX2 were developed as two recommended safe drug candidates.•CXCL17 and GPR35 indeed interact in Caco-2 cells.
Mycotoxin contamination is an ongoing and growing issue that can create health risks and even cause death. Unfortunately, there is currently a lack of specific therapy against mycotoxins with few side effects. On the other hand, the strategic expression of CXCL17 in mucosal tissues suggests that it may be involved in immune response when exposed to mycotoxins, but the exact role of CXCL17 remains largely unknown. Using Caco-2 as a cell model of the intestinal epithelial barrier (the first line of defense against mycotoxins), we showed that a strong production of ROS-dependent CXCL17 was triggered by mycotoxins via p38 and JNK pathways. Under the mycotoxins stress, CXCL17 modulated enhanced immuno-protective response with a remission of inflammation and apoptosis through PI3K/AKT/mTOR. Based on our observed feedback of CXCL17 to the mycotoxins, we developed the CXCL17-mimetic peptides in silico (CX1 and CX2) that possessed the safety and the capability to ameliorate mycotoxins-inducible inflammation and apoptosis. In this study, the identification of detoxifying feature of CXCL17 is a prominent addition to the chemokine field, pointing out a new direction for curing the mycotoxins-caused damage.