PMID- 33763056
OWN - NLM
STAT- MEDLINE
DCOM- 20210623
LR  - 20220103
IS  - 1664-3224 (Electronic)
IS  - 1664-3224 (Linking)
VI  - 11
DP  - 2020
TI  - Proteinase-Mediated Macrophage Signaling in Psoriatic Arthritis.
PG  - 629726
LID - 10.3389/fimmu.2020.629726 [doi]
LID - 629726
AB  - OBJECTIVE: Multiple proteinases are present in the synovial fluid (SF) of an 
      arthritic joint. We aimed to identify inflammatory cell populations present in 
      psoriatic arthritis (PsA) SF compared to osteoarthritis (OA) and rheumatoid 
      arthritis (RA), identify their proteinase-activated receptor 2 (PAR2) signaling 
      function and characterize potentially active SF serine proteinases that may be 
      PAR2 activators. METHODS: Flow cytometry was used to characterize SF cells from 
      PsA, RA, OA patients; PsA SF cells were further characterized by single cell 
      3'-RNA-sequencing. Active serine proteinases were identified through cleavage of 
      fluorogenic trypsin- and chymotrypsin-like substrates, activity-based probe 
      analysis and proteomics. Fluo-4 AM was used to monitor intracellular calcium cell 
      signaling. Cytokine expression was evaluated using a multiplex Luminex panel. 
      RESULTS: PsA SF cells were dominated by monocytes/macrophages, which consisted of 
      three populations representing classical, non-classical and intermediate cells. 
      The classical monocytes/macrophages were reduced in PsA compared to OA/RA, whilst 
      the intermediate population was increased. PAR2 was elevated in OA vs. PsA/RA SF 
      monocytes/macrophages, particularly in the intermediate population. PAR2 
      expression and signaling in primary PsA monocytes/macrophages significantly 
      impacted the production of monocyte chemoattractant protein-1 (MCP-1). 
      Trypsin-like serine proteinase activity was elevated in PsA and RA SF compared to 
      OA, while chymotrypsin-like activity was elevated in RA compared to PsA. 
      Tryptase-6 was identified as an active serine proteinase in SF that could trigger 
      calcium signaling partially via PAR2. CONCLUSION: PAR2 and its activating 
      proteinases, including tryptase-6, can be important mediators of inflammation in 
      PsA. Components within this proteinase-receptor axis may represent novel 
      therapeutic targets.
CI  - Copyright (c) 2021 Abji, Rasti, Gomez-Aristizabal, Muytjens, Saifeddine, Mihara, 
      Motahhari, Gandhi, Viswanathan, Hollenberg, Oikonomopoulou and Chandran.
FAU - Abji, Fatima
AU  - Abji F
AD  - Schroeder Arthritis Institute, Krembil Research Institute, University Health 
      Network, Toronto, ON, Canada.
FAU - Rasti, Mozhgan
AU  - Rasti M
AD  - Schroeder Arthritis Institute, Krembil Research Institute, University Health 
      Network, Toronto, ON, Canada.
FAU - Gomez-Aristizabal, Alejandro
AU  - Gomez-Aristizabal A
AD  - Schroeder Arthritis Institute, Krembil Research Institute, University Health 
      Network, Toronto, ON, Canada.
FAU - Muytjens, Carla
AU  - Muytjens C
AD  - Schroeder Arthritis Institute, Krembil Research Institute, University Health 
      Network, Toronto, ON, Canada.
FAU - Saifeddine, Mahmoud
AU  - Saifeddine M
AD  - Department of Physiology & Pharmacology, University of Calgary Cumming School of 
      Medicine, Calgary, AB, Canada.
FAU - Mihara, Koichiro
AU  - Mihara K
AD  - Department of Physiology & Pharmacology, University of Calgary Cumming School of 
      Medicine, Calgary, AB, Canada.
FAU - Motahhari, Majid
AU  - Motahhari M
AD  - Department of Physiology & Pharmacology, University of Calgary Cumming School of 
      Medicine, Calgary, AB, Canada.
FAU - Gandhi, Rajiv
AU  - Gandhi R
AD  - Schroeder Arthritis Institute, Krembil Research Institute, University Health 
      Network, Toronto, ON, Canada.
AD  - Division of Orthopaedic Surgery, Department of Surgery, Toronto Western Hospital, 
      Toronto, ON, Canada.
FAU - Viswanathan, Sowmya
AU  - Viswanathan S
AD  - Schroeder Arthritis Institute, Krembil Research Institute, University Health 
      Network, Toronto, ON, Canada.
AD  - Institute of Biomedical Engineering, University of Toronto, Toronto, ON, Canada.
AD  - Division of Hematology, Department of Medicine, University of Toronto, Toronto, 
      ON, Canada.
FAU - Hollenberg, Morley D
AU  - Hollenberg MD
AD  - Department of Physiology & Pharmacology, University of Calgary Cumming School of 
      Medicine, Calgary, AB, Canada.
AD  - Department of Medicine, University of Calgary Cumming School of Medicine, 
      Calgary, AB, Canada.
FAU - Oikonomopoulou, Katerina
AU  - Oikonomopoulou K
AD  - Schroeder Arthritis Institute, Krembil Research Institute, University Health 
      Network, Toronto, ON, Canada.
FAU - Chandran, Vinod
AU  - Chandran V
AD  - Schroeder Arthritis Institute, Krembil Research Institute, University Health 
      Network, Toronto, ON, Canada.
AD  - Division of Rheumatology, Department of Medicine, University of Toronto, Toronto, 
      ON, Canada.
AD  - Institute of Medical Science, University of Toronto, Toronto, ON, Canada.
AD  - Department of Laboratory Medicine and Pathobiology, University of Toronto, 
      Toronto, ON, Canada.
AD  - Department of Medicine, Memorial University of Newfoundland, St. John's, NL, 
      Canada.
LA  - eng
GR  - PJT 148565/CIHR/Canada
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20210308
PL  - Switzerland
TA  - Front Immunol
JT  - Frontiers in immunology
JID - 101560960
RN  - 0 (F2RL1 protein, human)
RN  - 0 (Receptor, PAR-2)
RN  - EC 3.4.21.59 (Tryptases)
SB  - IM
EIN - Front Immunol. 2021 Dec 15;12:814072. PMID: 34975926
MH  - Arthritis, Psoriatic/*immunology/pathology
MH  - Calcium Signaling/*immunology
MH  - Female
MH  - Humans
MH  - Macrophages/*immunology/pathology
MH  - Male
MH  - Receptor, PAR-2/*immunology
MH  - Tryptases/*immunology
PMC - PMC7982406
OTO - NOTNLM
OT  - PAR2
OT  - macrophage
OT  - monocyte
OT  - serine proteinase
OT  - spondyloarthritis
OT  - synovial fluid
OT  - tryptase-6
COIS- The authors declare that the research was conducted in the absence of any 
      commercial or financial relationships that could be construed as a potential 
      conflict of interest.
EDAT- 2021/03/26 06:00
MHDA- 2021/06/24 06:00
PMCR- 2020/01/01
CRDT- 2021/03/25 06:26
PHST- 2020/11/15 00:00 [received]
PHST- 2020/12/29 00:00 [accepted]
PHST- 2021/03/25 06:26 [entrez]
PHST- 2021/03/26 06:00 [pubmed]
PHST- 2021/06/24 06:00 [medline]
PHST- 2020/01/01 00:00 [pmc-release]
AID - 10.3389/fimmu.2020.629726 [doi]
PST - epublish
SO  - Front Immunol. 2021 Mar 8;11:629726. doi: 10.3389/fimmu.2020.629726. eCollection 
      2020.