title: Toll-like receptor 4 antagonist TAK-242 inhibits autoinflammatory symptoms in DITRA.
abstract: BACKGROUND
  IL36RN encodes the IL-36 receptor antagonist (IL-36Ra), and loss-of-function mutations in IL36RN define a recessively inherited autoinflammatory disease named "deficiency of IL-36Ra" (DITRA). DITRA causes systemic autoinflammatory diseases, including generalized pustular psoriasis (GPP), an occasionally life-threatening disease that is characterized by widespread sterile pustules on the skin, fever and other systemic symptoms. GPP can present at any age, and provocative factors include various infections, medicines and pregnancy.
  
  
  OBJECTIVE
  We aimed to elucidate the role of toll-like receptor 4 (TLR4) signaling in DITRA and to innovate an efficient treatment for DITRA.
  
  
  METHODS
  We generated Il36rn-/-mice and treated them with TLR4 agonist to establish DITRA model mice. Furthermore, we administrated TLR4 antagonist TAK-242 to the model mice to inhibit the DITRA symptoms.
  
  
  RESULTS
  Il36rn-/-mice treated by TLR4 agonist showed autoinflammatory symptoms in skin, articulation and liver. Thus, we established model mice for DITRA or GPP that show cutaneous, articular, and hepatic autoinflammatory symptoms typical of DITRA or GPP: sterile pustules on the skin, liver abscesses and enthesitis of the hind paws. Additionally, these symptoms were canceled by TAK-242 administration. We demonstrated the inhibitory effects of the TLR4 antagonist TAK-242 on the autoinflammatory symptoms exhibited by the DITRA models.
  
  
  CONCLUSIONS
  We suggested that blockage of TLR4 signaling is a promising treatment for DITRA and GPP.
authors.affiliation: Department of Dermatology, Nagoya University Graduate School of Medicine, Nagoya, Japan; Department of Dermatology, Gifu Prefectural Tajimi Hospital, Tajimi, Japan.
authors.forename: Akitaka
authors.initials: A
authors.lastname: Shibata
authors.affiliation: Department of Dermatology, Nagoya University Graduate School of Medicine, Nagoya, Japan; Department of Dermatology, Fujita Health University School of Medicine, Toyoake, Japan.
authors.forename: Kazumitsu
authors.initials: K
authors.lastname: Sugiura
authors.affiliation: Animal Resource Development Unit, RIKEN Center for Life Science Technologies, Kobe, Japan.
authors.forename: Yasuhide
authors.initials: Y
authors.lastname: Furuta
authors.affiliation: Animal Resource Development Unit, RIKEN Center for Life Science Technologies, Kobe, Japan; Genetic Engineering Team, RIKEN Center for Life Science Technologies, Kobe, Japan.
authors.forename: Yoshiko
authors.initials: Y
authors.lastname: Mukumoto
authors.affiliation: Department of Genome Medicine, Allergy and Immunology Project, Tokyo Metropolitan Institute of Medical Science, Tokyo, Japan; The Center for Life Science Research, University of Yamanashi, Chuo, Japan.
authors.forename: Osamu
authors.initials: O
authors.lastname: Kaminuma
authors.affiliation: Department of Dermatology, Nagoya University Graduate School of Medicine, Nagoya, Japan. Electronic address: makiyama@med.nagoya-u.ac.jp.
authors.forename: Masashi
authors.initials: M
authors.lastname: Akiyama
mesh_terms: D000818:Animals; D001327:Autoimmune Diseases / Q000188:drug therapy* / Q000235:genetics; D003677:Deficiency Diseases / Q000188:drug therapy* / Q000235:genetics; D004195:Disease Models, Animal; D006801:Humans; D007378:Interleukins / Q000235:genetics / Q000378:metabolism*; D007596:Joints / Q000473:pathology; D008070:Lipopolysaccharides / Q000008:administration & dosage; D008099:Liver / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D011565:Psoriasis / Q000188:drug therapy* / Q000235:genetics; D012867:Skin / Q000473:pathology*; D013449:Sulfonamides / Q000494:pharmacology / Q000627:therapeutic use*; D051197:Toll-Like Receptor 4 / Q000037:antagonists & inhibitors / Q000378:metabolism*
chemical_list: C122187:IL36RN protein, human; D007378:Interleukins; D008070:Lipopolysaccharides; D013449:Sulfonamides; C493487:Tlr4 protein, mouse; D051197:Toll-Like Receptor 4; C507035:ethyl 6-(N-(2-chloro-4-fluorophenyl)sulfamoyl)cyclohex-1-ene-1-carboxylate
keywords: Autoinflammation; Deficiency of IL-36 receptor antagonist; Generalized pustular psoriasis; LPS; TAK-242; Toll-like receptor 4