Andrographolide alleviates imiquimod-induced psoriasis in mice via inducing autophagic proteolysis of MyD88.
Psoriasis is a chronic inflammatory skin disease with excessive activation of toll-like receptors (TLRs), which play important roles in developing psoriasis. Targeting TLR signaling remains a challenge for treating psoriasis. Here, we found that andrographolide (Andro), a small-molecule natural product, alleviated imiquimod- but not interleukin 23 (IL-23)-induced psoriasis in mice with reducing expressions of IL-23 and IL-1β in the skin. The improvement in imiquimod-induced psoriasis by Andro was not observed in microtubule-associated protein 1 light chain 3 beta (MAP1LC3B) knockout mice. Furthermore, Andro inhibited mRNA expressions of IL-23, IL-6 and IL-1β but not CD80 and CD86 in bone-marrow derived dendritic cells (BMDCs) treated with lipopolysaccharide (LPS) in a MAP1LC3B-dependent manner. In addition, Andro inhibited imiquimod-induced mRNA expressions of IL-23, IL-6, IL-1β, CD80 and CD86 in BMDCs from mice. Interestingly, Andro induced a degradation of myeloid differentiation factor 88 (MyD88) and blocked the recruitment of TNF receptor-associated factor 6 (TRAF6) to MyD88 upon LPS stimulation in BMDCs from mice. Blockade of autophagic proteolysis using NH4Cl or MAP1LC3B(-/-) BMDCs abolished the Andro-induced MyD88 degradation. In conclusion, Andro controls activation of MyD88-dependent cytokines and alleviates psoriasis in mice via inducing autophagic proteolysis of MyD88, which could be a novel strategy to treat psoriasis.
State Key Laboratory of Pharmaceutical Biotechnology and Collaborative Innovation Center of Chemistry for Life Sciences, School of Life Sciences, Nanjing University, Nanjing 210023, China.
Fenli
F
Shao
State Key Laboratory of Pharmaceutical Biotechnology and Collaborative Innovation Center of Chemistry for Life Sciences, School of Life Sciences, Nanjing University, Nanjing 210023, China.
Tao
T
Tan
State Key Laboratory of Pharmaceutical Biotechnology and Collaborative Innovation Center of Chemistry for Life Sciences, School of Life Sciences, Nanjing University, Nanjing 210023, China.
Yang
Y
Tan
State Key Laboratory of Pharmaceutical Biotechnology and Collaborative Innovation Center of Chemistry for Life Sciences, School of Life Sciences, Nanjing University, Nanjing 210023, China.
Yang
Y
Sun
State Key Laboratory of Pharmaceutical Biotechnology and Collaborative Innovation Center of Chemistry for Life Sciences, School of Life Sciences, Nanjing University, Nanjing 210023, China. Electronic address: xingxin.wu@nju.edu.cn.
Xingxin
X
Wu
State Key Laboratory of Pharmaceutical Biotechnology and Collaborative Innovation Center of Chemistry for Life Sciences, School of Life Sciences, Nanjing University, Nanjing 210023, China. Electronic address: molpharm@163.com.
Qiang
Q
Xu
D000634:Aminoquinolines; D035685:Andrographis / Q000737:chemistry; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000627:therapeutic use*; D001343:Autophagy / Q000187:drug effects*; D004224:Diterpenes / Q000627:therapeutic use*; D004365:Drugs, Chinese Herbal / Q000627:therapeutic use*; D000077271:Imiquimod; D053583:Interleukin-1beta / Q000037:antagonists & inhibitors / Q000378:metabolism; D053759:Interleukin-23 / Q000037:antagonists & inhibitors / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D053594:Myeloid Differentiation Factor 88 / Q000378:metabolism*; D059748:Proteolysis / Q000187:drug effects; D011565:Psoriasis / Q000139:chemically induced / Q000188:drug therapy* / Q000378:metabolism; D012867:Skin / Q000187:drug effects / Q000378:metabolism; D048029:TNF Receptor-Associated Factor 6 / Q000378:metabolism
D000634:Aminoquinolines; D000894:Anti-Inflammatory Agents, Non-Steroidal; D004224:Diterpenes; D004365:Drugs, Chinese Herbal; D053583:Interleukin-1beta; D053759:Interleukin-23; C507780:Myd88 protein, mouse; D053594:Myeloid Differentiation Factor 88; D048029:TNF Receptor-Associated Factor 6; C030419:andrographolide; D000077271:Imiquimod
Andrographolide; BMDC; MyD88; Proinflammatory cytokine; Psoriasis