PMID- 31895698
OWN - NLM
STAT- MEDLINE
DCOM- 20201230
LR  - 20201230
IS  - 1558-8238 (Electronic)
IS  - 0021-9738 (Print)
IS  - 0021-9738 (Linking)
VI  - 130
IP  - 4
DP  - 2020 Apr 1
TI  - Bruton tyrosine kinase deficiency augments NLRP3 inflammasome activation and 
      causes IL-1beta-mediated colitis.
PG  - 1793-1807
LID - 128322 [pii]
LID - 10.1172/JCI128322 [doi]
AB  - Bruton tyrosine kinase (BTK) is present in a wide variety of cells and may thus 
      have important non-B cell functions. Here, we explored the function of this 
      kinase in macrophages with studies of its regulation of the NLR family, pyrin 
      domain-containing 3 (NLRP3) inflammasome. We found that bone marrow-derived 
      macrophages (BMDMs) from BTK-deficient mice or monocytes from patients with 
      X-linked agammaglobulinemia (XLA) exhibited increased NLRP3 inflammasome 
      activity; this was also the case for BMDMs exposed to low doses of BTK inhibitors 
      such as ibrutinib and for monocytes from patients with chronic lymphocytic 
      leukemia being treated with ibrutinib. In mechanistic studies, we found that BTK 
      bound to NLRP3 during the priming phase of inflammasome activation and, in doing 
      so, inhibited LPS- and nigericin-induced assembly of the NLRP3 inflammasome 
      during the activation phase of inflammasome activation. This inhibitory effect 
      was caused by BTK inhibition of protein phosphatase 2A-mediated (PP2A-mediated) 
      dephosphorylation of Ser5 in the pyrin domain of NLRP3. Finally, we show that 
      BTK-deficient mice were subject to severe experimental colitis and that such 
      colitis was normalized by administration of anti-IL-beta or anakinra, an inhibitor 
      of IL-1beta signaling. Together, these studies strongly suggest that BTK functions 
      as a physiologic inhibitor of NLRP3 inflammasome activation and explain why 
      patients with XLA are prone to develop Crohn's disease.
FAU - Mao, Liming
AU  - Mao L
AD  - Mucosal Immunity Section, Laboratory of Clinical Immunology and Microbiology, 
      National Institute of Allergy and Infectious Diseases (NIAID), NIH, Bethesda, 
      Maryland, USA.
FAU - Kitani, Atsushi
AU  - Kitani A
AD  - Mucosal Immunity Section, Laboratory of Clinical Immunology and Microbiology, 
      National Institute of Allergy and Infectious Diseases (NIAID), NIH, Bethesda, 
      Maryland, USA.
FAU - Hiejima, Eitaro
AU  - Hiejima E
AD  - Mucosal Immunity Section, Laboratory of Clinical Immunology and Microbiology, 
      National Institute of Allergy and Infectious Diseases (NIAID), NIH, Bethesda, 
      Maryland, USA.
FAU - Montgomery-Recht, Kim
AU  - Montgomery-Recht K
AD  - Clinical Research Directorate/Clinical Monitoring Research Program, Leidos 
      Biomedical Research Inc., National Cancer Institute (NCI) Campus at Frederick, 
      Frederick, Maryland, USA.
FAU - Zhou, Wenchang
AU  - Zhou W
AD  - Theoretical Molecular Biophysics Laboratory, National Heart, Lung and Blood 
      Institute (NHLBI), and.
FAU - Fuss, Ivan
AU  - Fuss I
AD  - Mucosal Immunity Section, Laboratory of Clinical Immunology and Microbiology, 
      National Institute of Allergy and Infectious Diseases (NIAID), NIH, Bethesda, 
      Maryland, USA.
FAU - Wiestner, Adrian
AU  - Wiestner A
AD  - Lymphoid Malignancies Section, Hematology Branch, NHLBI, NIH, Bethesda, Maryland, 
      USA.
FAU - Strober, Warren
AU  - Strober W
AD  - Mucosal Immunity Section, Laboratory of Clinical Immunology and Microbiology, 
      National Institute of Allergy and Infectious Diseases (NIAID), NIH, Bethesda, 
      Maryland, USA.
LA  - eng
GR  - HHSN261200800001E/CA/NCI NIH HHS/United States
GR  - ZIA AI000354/ImNIH/Intramural NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, N.I.H., Intramural
PL  - United States
TA  - J Clin Invest
JT  - The Journal of clinical investigation
JID - 7802877
RN  - 0 (IL1B protein, human)
RN  - 0 (IL1B protein, mouse)
RN  - 0 (Inflammasomes)
RN  - 0 (Interleukin-1beta)
RN  - 0 (NLR Family, Pyrin Domain-Containing 3 Protein)
RN  - 0 (NLRP3 protein, human)
RN  - 0 (Nlrp3 protein, mouse)
RN  - EC 2.7.10.2 (Agammaglobulinaemia Tyrosine Kinase)
RN  - EC 2.7.10.2 (BTK protein, human)
RN  - EC 2.7.10.2 (Btk protein, mouse)
RN  - Bruton type agammaglobulinemia
SB  - IM
MH  - Adolescent
MH  - Adult
MH  - Agammaglobulinaemia Tyrosine Kinase/*deficiency/metabolism
MH  - Agammaglobulinemia/enzymology/genetics/pathology
MH  - Aged
MH  - Aged, 80 and over
MH  - Animals
MH  - Child
MH  - *Crohn Disease/enzymology/genetics/pathology
MH  - Female
MH  - Genetic Diseases, X-Linked/enzymology/genetics/pathology
MH  - Humans
MH  - Inflammasomes/genetics/*metabolism
MH  - Interleukin-1beta/genetics/*metabolism
MH  - Male
MH  - Mice
MH  - Mice, Knockout
MH  - NLR Family, Pyrin Domain-Containing 3 Protein/genetics/*metabolism
PMC - PMC7108929
OTO - NOTNLM
OT  - Gastroenterology
OT  - Inflammatory bowel disease
OT  - Innate immunity
COIS- Conflict of interest: AW receives research funding from Pharmacyclics, an AbbVie 
      Company.
EDAT- 2020/01/03 06:00
MHDA- 2020/12/31 06:00
PMCR- 2020/07/01
CRDT- 2020/01/03 06:00
PHST- 2019/03/25 00:00 [received]
PHST- 2019/12/23 00:00 [accepted]
PHST- 2020/01/03 06:00 [pubmed]
PHST- 2020/12/31 06:00 [medline]
PHST- 2020/01/03 06:00 [entrez]
PHST- 2020/07/01 00:00 [pmc-release]
AID - 128322 [pii]
AID - 10.1172/JCI128322 [doi]
PST - ppublish
SO  - J Clin Invest. 2020 Apr 1;130(4):1793-1807. doi: 10.1172/JCI128322.