PMID- 34995358
OWN - NLM
STAT- MEDLINE
DCOM- 20220701
LR  - 20220830
IS  - 1398-9995 (Electronic)
IS  - 0105-4538 (Linking)
VI  - 77
IP  - 7
DP  - 2022 Jul
TI  - Thrombin cleaves IL-33 and modulates IL-33-activated allergic lung inflammation.
PG  - 2104-2120
LID - 10.1111/all.15210 [doi]
AB  - BACKGROUND: Organisms have orchestrated coagulation and immune systems. Although 
      a link between inflammation and haemostasis has been reported in asthma, the 
      interaction mechanism has not been completely elucidated. Here, we investigated 
      the direct link between the mammalian immune and coagulation systems. METHODS: 
      Mice were administered protease or antigens intranasally to induce airway 
      inflammation with or without thrombin inhibitors treatment. The effects of 
      thrombin and its inhibitors on interleukin (IL)-33 were investigated both in vivo 
      and in vitro. Peripheral blood mononuclear cells (PBMCs) and plasma from asthma 
      patients are collected to verify the correlation between thrombin and group 2 
      innate lymphocytes (ILC2s). RESULTS: Low-molecular-weight heparin (LMWH, an 
      indirect inhibitor of thrombin) restrained both papain- and fungus-induced type 2 
      immune responses in mice by inhibiting IL-33 cleavage. Upon examining the 
      potential thrombin protease consensus sites, we found that IL-33 was directly 
      cleaved by thrombin at specific amino acids (R48 and R106) to generate a mature 
      form of IL-33 with potent biological activity. In addition, we found that 
      bivalirudin TFA (a direct inhibitor of thrombin) inhibited a variety of type 2 
      inflammatory responses, such as those in house dust mite (HDM)- and ovalbumin 
      (OVA)-mediated pulmonary inflammation models. We found that plasma 
      thrombin-antithrombin complex (TATc) levels in asthma patients were positively 
      associated with the number and function of IL-33-responder group 2 innate 
      lymphocytes (ILC2s) among peripheral blood mononuclear cells (PBMCs) from asthma 
      patients. CONCLUSION: The data suggested that thrombin inhibitors administration 
      could be effective in treating lung inflammation by regulating ILC2s via 
      IL-33 maturation, indicating that targeting thrombin is a potential way to treat 
      allergic diseases.
CI  - (c) 2022 European Academy of Allergy and Clinical Immunology and John Wiley & Sons 
      Ltd.
FAU - Huang, Yuying
AU  - Huang Y
AD  - State Key Laboratory of Cell Biology, CAS Center for Excellence in Molecular Cell 
      Science, Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of 
      Sciences, University of Chinese Academy of Sciences, Shanghai, China.
FAU - Li, Xuezhen
AU  - Li X
AD  - State Key Laboratory of Cell Biology, CAS Center for Excellence in Molecular Cell 
      Science, Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of 
      Sciences, University of Chinese Academy of Sciences, Shanghai, China.
FAU - Zhu, Lin
AU  - Zhu L
AD  - State Key Laboratory of Cell Biology, CAS Center for Excellence in Molecular Cell 
      Science, Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of 
      Sciences, University of Chinese Academy of Sciences, Shanghai, China.
FAU - Huang, Chunrong
AU  - Huang C
AD  - Department of Respiratory and Critical Care Medicine, Ruijin Hospital, Shanghai 
      Jiao Tong University School of Medicine, Shanghai, China.
FAU - Chen, Wen
AU  - Chen W
AD  - State Key Laboratory of Cell Biology, CAS Center for Excellence in Molecular Cell 
      Science, Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of 
      Sciences, University of Chinese Academy of Sciences, Shanghai, China.
FAU - Ling, Zhiyang
AU  - Ling Z
AD  - State Key Laboratory of Cell Biology, CAS Center for Excellence in Molecular Cell 
      Science, Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of 
      Sciences, University of Chinese Academy of Sciences, Shanghai, China.
FAU - Zhu, SongLing
AU  - Zhu S
AD  - State Key Laboratory of Cell Biology, CAS Center for Excellence in Molecular Cell 
      Science, Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of 
      Sciences, University of Chinese Academy of Sciences, Shanghai, China.
FAU - Feng, Xintong
AU  - Feng X
AD  - Unit of Respiratory Infection and Immunity, Chinese Academy of Sciences, 
      Institute Pasteur of Shanghai, Shanghai, China.
FAU - Yi, Chunyan
AU  - Yi C
AD  - State Key Laboratory of Cell Biology, CAS Center for Excellence in Molecular Cell 
      Science, Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of 
      Sciences, University of Chinese Academy of Sciences, Shanghai, China.
FAU - Gu, Wangpeng
AU  - Gu W
AD  - State Key Laboratory of Cell Biology, CAS Center for Excellence in Molecular Cell 
      Science, Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of 
      Sciences, University of Chinese Academy of Sciences, Shanghai, China.
FAU - Yan, Chenghua
AU  - Yan C
AD  - State Key Laboratory of Cell Biology, CAS Center for Excellence in Molecular Cell 
      Science, Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of 
      Sciences, University of Chinese Academy of Sciences, Shanghai, China.
FAU - Wang, Jing
AU  - Wang J
AD  - Department of Respiratory Medicine, First Affiliated Hospital of Xinjiang Medical 
      University, Wulumuqi, China.
FAU - Ma, Liyan
AU  - Ma L
AD  - State Key Laboratory of Cell Biology, CAS Center for Excellence in Molecular Cell 
      Science, Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of 
      Sciences, University of Chinese Academy of Sciences, Shanghai, China.
FAU - Su, Xiao
AU  - Su X
AD  - Unit of Respiratory Infection and Immunity, Chinese Academy of Sciences, 
      Institute Pasteur of Shanghai, Shanghai, China.
FAU - Dai, Ranran
AU  - Dai R
AD  - Department of Respiratory and Critical Care Medicine, Ruijin Hospital, Shanghai 
      Jiao Tong University School of Medicine, Shanghai, China.
FAU - Shi, Guochao
AU  - Shi G
AD  - Department of Respiratory and Critical Care Medicine, Ruijin Hospital, Shanghai 
      Jiao Tong University School of Medicine, Shanghai, China.
FAU - Sun, Bing
AU  - Sun B
AD  - State Key Laboratory of Cell Biology, CAS Center for Excellence in Molecular Cell 
      Science, Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of 
      Sciences, University of Chinese Academy of Sciences, Shanghai, China.
FAU - Zhang, Yaguang
AU  - Zhang Y
AUID- ORCID: 0000-0002-2417-6516
AD  - State Key Laboratory of Cell Biology, CAS Center for Excellence in Molecular Cell 
      Science, Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of 
      Sciences, University of Chinese Academy of Sciences, Shanghai, China.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20220112
PL  - Denmark
TA  - Allergy
JT  - Allergy
JID - 7804028
RN  - 0 (Cytokines)
RN  - 0 (Heparin, Low-Molecular-Weight)
RN  - 0 (Interleukin-33)
RN  - EC 3.4.21.5 (Thrombin)
SB  - IM
MH  - *Alveolitis, Extrinsic Allergic
MH  - Animals
MH  - *Asthma
MH  - Cytokines/metabolism
MH  - Heparin, Low-Molecular-Weight/metabolism/pharmacology
MH  - Immunity, Innate
MH  - Inflammation/metabolism
MH  - Interleukin-33/metabolism
MH  - Leukocytes, Mononuclear/metabolism
MH  - Lung
MH  - Lymphocytes
MH  - Mice
MH  - *Pulmonary Eosinophilia
MH  - Thrombin/metabolism/pharmacology
OTO - NOTNLM
OT  - IL-33
OT  - asthma
OT  - group 2 innate lymphoid cell
OT  - thrombin
EDAT- 2022/01/08 06:00
MHDA- 2022/07/02 06:00
CRDT- 2022/01/07 17:24
PHST- 2021/11/19 00:00 [revised]
PHST- 2021/10/05 00:00 [received]
PHST- 2021/12/11 00:00 [accepted]
PHST- 2022/01/08 06:00 [pubmed]
PHST- 2022/07/02 06:00 [medline]
PHST- 2022/01/07 17:24 [entrez]
AID - 10.1111/all.15210 [doi]
PST - ppublish
SO  - Allergy. 2022 Jul;77(7):2104-2120. doi: 10.1111/all.15210. Epub 2022 Jan 12.