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Cited by 10Transplantation: Methods and OutcomesCardiac Fibrosis and RemodelingOrgan and Tissue Transplantation Research

Prolyl endopeptidase contributes to early neutrophilic inflammation in acute myocardial transplant rejection

Open access
Payne, Gregory A., Sharma, Nirmal S., Lal, Charitharth V., Song, Chunyan, Guo, Lingling, Margaroli, Camilla, Viera, Liliana, Kumar, Siva +10 more·2021·JCI Insight
DOI 10.1172/jci.insight.139687PMC PMC8026194
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Abstract

Altered inflammation and tissue remodeling are cardinal features of cardiovascular disease and cardiac transplant rejection. Neutrophils have increasingly been understood to play a critical role in acute rejection and early allograft failure; however, discrete mechanisms that drive this damage remain poorly understood. Herein, we demonstrate that early acute cardiac rejection increases allograft prolyl endopeptidase (PE) in association with de novo production of the neutrophil proinflammatory matrikine proline-glycine-proline (PGP). In a heterotopic murine heart transplant model, PGP production and PE activity were associated with early neutrophil allograft invasion and allograft failure. Pharmacologic inhibition of PE with Z-Pro-prolinal reduced PGP, attenuated early neutrophil graft invasion, and reduced proinflammatory cytokine expression. Importantly, these changes helped preserve allograft rejection-free survival and function. Notably, within 2 independent patient cohorts, both PGP and PE activity were increased among patients with biopsy-proven rejection. The observed induction of PE and matrikine generation provide a link between neutrophilic inflammation and cardiovascular injury, represent a potential target to reduce allogenic immune responses, and uncover a mechanism of cardiovascular disease that has been previously unrecognized to our knowledge.

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  • Unrestricted release of PGP motives in the transplantation of organs such as heart and lung mediates chronic inflammation and rejection.

    “Unrestricted release of PGP motives in the transplantation of organs such as heart and lung mediate chronic inflammation and rejection [102, 103].”

    From Immunogenicity of decellularized extracellular matrix scaffolds: a bottleneck in tissue engineering and regenerative medicine (2023) · cites this paper as [103]

    The Results section associates increased PGP with acute rejection in two heart-transplant patient cohorts, and the Discussion describes PGP as a contributor to neutrophilic inflammation in acute rejection. The paper does not establish this claim for lung transplants or chronic rejection; it also says PGP’s causal role in rejection needs further validation. Page numbers are unavailable in our copy. (LLM, conf=0.88)

    Experimental — accuracy not yet measured

  • MMPs degrade collagens and expose cryptic three-peptide motives PGP, which trigger CXCR2 receptors of neutrophils and orchestrate their chemotaxis and interplay with adaptive immunity.

    “MMPs per se degrade collagens and expose cryptic three-peptide motives PGP (Pro-Gly-Pro), which trigger CXCR2 receptors of neutrophils and orchestrate their chemotaxis and interplay with adaptive immunity.”

    From Immunogenicity of decellularized extracellular matrix scaffolds: a bottleneck in tissue engineering and regenerative medicine (2023) · cites this paper as [103]

    The Introduction (page unavailable) says collagen degradation produces PGP through the sequential action of MMPs and prolyl endopeptidase, and the Discussion identifies PGP as a CXCR2 ligand and neutrophil chemoattractant. The claim overstates MMPs acting on their own to produce PGP. The Discussion also treats a link between prolyl endopeptidase activity and adaptive immunity as tentative; it does not establish that PGP orchestrates that interplay. (LLM, conf=0.87)

    Experimental — accuracy not yet measured

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Research works printed but not linked: 28

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Authors
Payne, G. A., Sharma, N. S., Lal, C. V., Song, C., Guo, L., Margaroli, C., Viera, L., Kumar, S., Li, J., Xing, D., Bosley, M., Xu, X., Wells, J. M., George, J. F., Tallaj, J., Leesar, M., Blalock, J. E., & Gaggar, A.
Affiliations
  • University of Alabama at Birmingham (US)
  • Brigham and Women's Hospital (US)
  • Division of Cardiovascular Disease, Department of Medicine,
  • Department of Surgery,
  • University of South Florida (US)
  • Tampa General Hospital (US)
  • Comprehensive Cardiovascular (US)
Corresponding author
Payne, Gregory A.
ORCID
Venue
JCI Insight
Publisher
American Society for Clinical Investigation
Published
2021-03-22
Volume
6
Issue
6
ISSN
2379-3708 (ISSN-L)
DOI
10.1172/jci.insight.139687
PMC
PMC8026194
OpenAlex
W3128317405
Cited by
10
References
2
Citations by year
2026: 4 · 2025: 3 · 2023: 3
FWCI
0.70
Type
journal article
Language
en
Open access
Licence
Locations
  • JCI Insight (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
  • American Heart Association (18AMFDP34380568, 16SDG27040000)
  • National Heart, Lung, and Blood Institute (T32HL007457, 3R35HL135710-03S1, R35HL135710, R01HL102371, R01HL126596)
  • U.S. Department of Veterans Affairs (I01BX001756-02)
  • National Institute of Diabetes and Digestive and Kidney Diseases (P30 DK079337)
Topics
  • Health Sciences › Medicine › Surgery › Transplantation: Methods and Outcomes
  • Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Cardiac Fibrosis and Remodeling
  • Health Sciences › Medicine › Transplantation › Organ and Tissue Transplantation Research
Keywords
prolyl endopeptidase, matrikines, neutrophils, allograft rejection, neutrophilic inflammation, allograft failure, inflammatory cytokines, heart transplantation, cardiovascular damage
MeSH terms
Prolyl Oligopeptidases, Adult, Aged, Animals, Female, Graft Rejection, Humans, Male, Middle Aged, Neutrophils, Heart Transplantation, Critical Pathways, Mice

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