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

Payne, Gregory A.; Sharma, Nirmal; Lal, Charitharth Vivek; Song, Chun-Yan; Guo, Lingling; Margaroli, Camilla; Viera, Liliana; Kumar, Siva; Li, Jindong; Xing, Dong; Bosley, Melanie; Xu, Xin; Wells, James M.; George, James F.; Tallaj, José; Leesar, Massoud A.; Blalock, J. Edwin; Gaggar, Amit

doi:10.1172/jci.insight.139687

Cited by 4 publications

(3 citation statements)

References 29 publications

(44 reference statements)

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“…57 Similar to TNF-α gene expression, IFN-γ was induced at an early time point posttransplantation. 58 This may help explain why DT-061 has little effect on mRNA levels of TNF-α and IFN-γ on day 6 posttransplantation. In addition, TGF-β1 is a prerequisite for the induction of Foxp3 expression in CD4 + T cell and differentiation into Treg.…”

Section: Discussionmentioning

confidence: 99%

Protein Phosphatase 2A Activation Promotes Heart Transplant Acceptance in Mice

Zhou,

Xu,

et al. 2023

Transplantation

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Background. Although heart transplantation is the definitive treatment for heart failure in eligible patients, both acute and chronic transplant rejection frequently occur. Protein phosphatase 2A (PP2A) activity is critical in maintaining tissue and organ homeostasis. In this study, we evaluated the effect of a novel class of small molecule activators of PP2A (SMAPs) on allograft rejection in a mouse heterotopic heart transplantation model. Methods. Recipient mice were administered with DT-061 (a pharmaceutically optimized SMAP) or vehicle by oral gavage beginning 1 d after transplantation. Histological and immunofluorescence analyses were performed to examine allograft rejection. Regulatory T cells (Treg) from recipient spleens were subjected to flow cytometry and RNA sequencing analysis. Finally, the effect of DT-061 on smooth muscle cells (SMCs) migration and proliferation was assessed. Results. DT-061 treatment prolonged cardiac allograft survival. SMAPs effectively suppressed the inflammatory immune response while increasing Treg population in the allografts, findings corroborated by functional analysis of RNA sequencing data derived from Treg of treated splenic tissues. Importantly, SMAPs extended immunosuppressive agent cytotoxic T lymphocyte–associated antigen-4-Ig–induced cardiac transplantation tolerance and allograft survival. SMAPs also strongly mitigated cardiac allograft vasculopathy as evidenced by a marked reduction of neointimal hyperplasia and SMC proliferation. Finally, our in vitro studies implicate suppression of MEK/ERK pathways as a unifying mechanism for the effect of PP2A modulation in Treg and SMCs. Conclusions. PP2A activation prevents cardiac rejection and prolongs allograft survival in a murine model. Our findings highlight the potential of PP2A activation in improving alloengraftment in heart transplantation.

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Section: Discussionmentioning

confidence: 99%

Protein Phosphatase 2A Activation Promotes Heart Transplant Acceptance in Mice

Zhou,

Xu,

et al. 2023

Transplantation

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“…Some latent laminin motifs of p.serosum induce chemotaxis of macrophages and neutrophils and increase MMP activity [ 60 ]. Furthermore, immune cells and MMPs can destroy the ECM and expose the three-peptide motifs of PGP (Pro-Gly-Pro), which trigger the CXCR2 receptors of neutrophils, control their chemotaxis, and initiate interactions with cells of adaptive immunity [ 22 , 61 ]. This is how the formation of a vicious circle occurs, leading to the establishment of chronic inflammation and the utilization of biological material that was shown for Groups A1, A2, M1, and M2.…”

Section: Discussionmentioning

confidence: 99%

Soft Biomimetic Approach for the Development of Calcinosis-Resistant Glutaraldehyde-Fixed Biomaterials for Cardiovascular Surgery

Zvyagina,

Minaychev,

Kobyakova

et al. 2023

Biomimetics

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Pathological aseptic calcification is the most common form of structural valvular degeneration (SVD), leading to premature failure of heart valve bioprostheses (BHVs). The processing methods used to obtain GA-fixed pericardium-based biomaterials determine the hemodynamic characteristics and durability of BHVs. This article presents a comparative study of the effects of several processing methods on the degree of damage to the ECM of GA-fixed pericardium-based biomaterials as well as on their biostability, biocompatibility, and resistance to calcification. Based on the assumption that preservation of the native ECM structure will enable the creation of calcinosis-resistant materials, this study provides a soft biomimetic approach for the manufacture of GA-fixed biomaterials using gentle decellularization and washing methods. It has been shown that the use of soft methods for preimplantation processing of materials, ensuring maximum preservation of the intactness of the pericardial ECM, radically increases the resistance of biomaterials to calcification. These obtained data are of interest for the development of new calcinosis-resistant biomaterials for the manufacture of BHVs.

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

Section: The Role Of Ecm Alteration In the Immunogenicity Of Decellul...mentioning

confidence: 99%

Immunogenicity of decellularized extracellular matrix scaffolds: a bottleneck in tissue engineering and regenerative medicine

et al. 2023

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Tissue-engineered decellularized extracellular matrix (ECM) scaffolds hold great potential to address the donor shortage as well as immunologic rejection attributed to cells in conventional tissue/organ transplantation. Decellularization, as the key process in manufacturing ECM scaffolds, removes immunogen cell materials and significantly alleviates the immunogenicity and biocompatibility of derived scaffolds. However, the application of these bioscaffolds still confronts major immunologic challenges. This review discusses the interplay between damage-associated molecular patterns (DAMPs) and antigens as the main inducers of innate and adaptive immunity to aid in manufacturing biocompatible grafts with desirable immunogenicity. It also appraises the impact of various decellularization methodologies (i.e., apoptosis-assisted techniques) on provoking immune responses that participate in rejecting allogenic and xenogeneic decellularized scaffolds. In addition, the key research findings regarding the contribution of ECM alterations, cytotoxicity issues, graft sourcing, and implantation site to the immunogenicity of decellularized tissues/organs are comprehensively considered. Finally, it discusses practical solutions to overcome immunogenicity, including antigen masking by crosslinking, sterilization optimization, and antigen removal techniques such as selective antigen removal and sequential antigen solubilization.

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

Cited by 4 publications

References 29 publications

Protein Phosphatase 2A Activation Promotes Heart Transplant Acceptance in Mice

Protein Phosphatase 2A Activation Promotes Heart Transplant Acceptance in Mice

Soft Biomimetic Approach for the Development of Calcinosis-Resistant Glutaraldehyde-Fixed Biomaterials for Cardiovascular Surgery

Immunogenicity of decellularized extracellular matrix scaffolds: a bottleneck in tissue engineering and regenerative medicine

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