PMID- 35978195
OWN - NLM
STAT- MEDLINE
DCOM- 20220909
LR  - 20230525
IS  - 1476-4687 (Electronic)
IS  - 0028-0836 (Print)
IS  - 0028-0836 (Linking)
VI  - 609
IP  - 7926
DP  - 2022 Sep
TI  - LACC1 bridges NOS2 and polyamine metabolism in inflammatory macrophages.
PG  - 348-353
LID - 10.1038/s41586-022-05111-3 [doi]
AB  - The mammalian immune system uses various pattern recognition receptors to 
      recognize invaders and host damage and transmits this information to downstream 
      immunometabolic signalling outcomes. Laccase domain-containing 1 (LACC1) protein 
      is an enzyme highly expressed in inflammatory macrophages and serves a central 
      regulatory role in multiple inflammatory diseases such as inflammatory bowel 
      diseases, arthritis and clearance of microbial infection(1-4). However, the 
      biochemical roles required for LACC1 functions remain largely undefined. Here we 
      elucidated a shared biochemical function of LACC1 in mice and humans, converting 
      L-citrulline to L-ornithine (L-Orn) and isocyanic acid and serving as a bridge 
      between proinflammatory nitric oxide synthase (NOS2) and polyamine 
      immunometabolism. We validated the genetic and mechanistic connections among 
      NOS2, LACC1 and ornithine decarboxylase 1 (ODC1) in mouse models and bone 
      marrow-derived macrophages infected by Salmonella enterica Typhimurium. 
      Strikingly, LACC1 phenotypes required upstream NOS2 and downstream ODC1, and 
      Lacc1(-/-) chemical complementation with its product L-Orn significantly restored 
      wild-type activities. Our findings illuminate a previously unidentified pathway 
      in inflammatory macrophages, explain why its deficiency may contribute to human 
      inflammatory diseases and suggest that L-Orn could serve as a nutraceutical to 
      ameliorate LACC1-associated immunological dysfunctions such as arthritis or 
      inflammatory bowel disease.
CI  - (c) 2022. The Author(s), under exclusive licence to Springer Nature Limited.
FAU - Wei, Zheng
AU  - Wei Z
AUID- ORCID: 0000-0002-1859-0374
AD  - Department of Immunobiology, Yale University School of Medicine, New Haven, CT, 
      USA.
AD  - Institute of Biomolecular Design & Discovery, Yale University, West Haven, CT, 
      USA.
FAU - Oh, Joonseok
AU  - Oh J
AD  - Institute of Biomolecular Design & Discovery, Yale University, West Haven, CT, 
      USA.
AD  - Department of Chemistry, Yale University, New Haven, CT, USA.
FAU - Flavell, Richard A
AU  - Flavell RA
AUID- ORCID: 0000-0003-4461-0778
AD  - Department of Immunobiology, Yale University School of Medicine, New Haven, CT, 
      USA. richard.flavell@yale.edu.
AD  - Howard Hughes Medical Institute, Yale University School of Medicine, New Haven, 
      CT, USA. richard.flavell@yale.edu.
FAU - Crawford, Jason M
AU  - Crawford JM
AUID- ORCID: 0000-0002-7583-1242
AD  - Institute of Biomolecular Design & Discovery, Yale University, West Haven, CT, 
      USA. jason.crawford@yale.edu.
AD  - Department of Chemistry, Yale University, New Haven, CT, USA. 
      jason.crawford@yale.edu.
AD  - Department of Microbial Pathogenesis, Yale University School of Medicine, New 
      Haven, CT, USA. jason.crawford@yale.edu.
LA  - eng
GR  - HHMI/Howard Hughes Medical Institute/United States
GR  - UL1 TR001863/TR/NCATS NIH HHS/United States
GR  - 1016720/WT_/Wellcome Trust/United Kingdom
PT  - Journal Article
DEP - 20220817
PL  - England
TA  - Nature
JT  - Nature
JID - 0410462
RN  - 0 (Cyanates)
RN  - 0 (Intracellular Signaling Peptides and Proteins)
RN  - 0 (LACC1 protein, human)
RN  - 0 (Lacc1 protein, mouse)
RN  - 0 (Polyamines)
RN  - 29VT07BGDA (Citrulline)
RN  - E524N2IXA3 (Ornithine)
RN  - EC 1.14.13.39 (NOS2 protein, human)
RN  - EC 1.14.13.39 (Nitric Oxide Synthase Type II)
RN  - EC 1.14.13.39 (Nos2 protein, mouse)
RN  - EC 4.1.1.17 (Ornithine Decarboxylase)
RN  - QKG6U31925 (isocyanic acid)
SB  - IM
EIN - Nature. 2023 Jun;618(7965):E21. PMID: 37231312
MH  - Animals
MH  - Arthritis/immunology/metabolism
MH  - Citrulline/metabolism
MH  - Cyanates/metabolism
MH  - Humans
MH  - *Inflammation/enzymology/immunology/metabolism
MH  - Inflammatory Bowel Diseases/immunology/metabolism
MH  - *Intracellular Signaling Peptides and Proteins/metabolism
MH  - *Macrophages/immunology/metabolism
MH  - Mice
MH  - *Nitric Oxide Synthase Type II/metabolism
MH  - Ornithine/metabolism
MH  - Ornithine Decarboxylase/metabolism
MH  - Polyamines/metabolism
MH  - Salmonella typhimurium/immunology
PMC - PMC9813773
MID - NIHMS1831020
EDAT- 2022/08/18 06:00
MHDA- 2022/09/11 06:00
PMCR- 2023/01/05
CRDT- 2022/08/17 23:33
PHST- 2021/07/11 00:00 [received]
PHST- 2022/07/14 00:00 [accepted]
PHST- 2022/08/18 06:00 [pubmed]
PHST- 2022/09/11 06:00 [medline]
PHST- 2022/08/17 23:33 [entrez]
PHST- 2023/01/05 00:00 [pmc-release]
AID - 10.1038/s41586-022-05111-3 [pii]
AID - 10.1038/s41586-022-05111-3 [doi]
PST - ppublish
SO  - Nature. 2022 Sep;609(7926):348-353. doi: 10.1038/s41586-022-05111-3. Epub 2022 
      Aug 17.