Presence of PTPN2 SNP rs1893217 Enhances the Anti-inflammatory Effect of Spermidine

Niechcial, Anna; Butter, Matthias; Manz, Salomon; Obialo, Nicole; Bäbler, Katharina; Lely, Lisa van der; Lang, Silvia; Gottier, Claudia; McCole, Declan F.; Scharl, Michael; Spalinger, Marianne R.

doi:10.1093/ibd/izaa013

Cited by 6 publications

(7 citation statements)

References 41 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In inflammatory disease models, spermidine was shown to have significant anti-inflammatory effects making it a promising candidate for use as a therapeutic agent. It inhibited skin inflammation and macrophage activation in mice, blocked NF-kB and MAPK signaling pathways, reduced pro-inflammatory genes and cytokines expression, modulated M1/M2 macrophage markers, [27,28,44,45].…”

Section: Discussionmentioning

confidence: 97%

“…Spermidine treatment also decreased expression of the pro-inflammatory cytokine, IFN-γ, and its pro-inflammatory target genes, ICAM-1 and NOD2 [27]. These effects were also found to be greater in cells with the PTPN2:rs1893217-G SNP compared to wild-type cells [27]. Another study investigated spermidine's ability and mechanism in treating acute colitis in mice [28].…”

Section: Introductionmentioning

confidence: 97%

“…Recent research has investigated the effect of treating human intestinal epithelial cells with the PTPN2:rs1893217-G SNP that is a risk factor for inflammatory bowel disease (IBD) with different polyamines [27]. They found the natural occurring polyamine, spermidine, was most effective in increasing PTPN2 expression and activating its phosphatase activity, as well as reducing STAT1 and STAT3 phosphorylation by IFN-γ which indicates its ability to suppress pro-inflammatory signaling cascades [27]. Spermidine treatment also decreased expression of the pro-inflammatory cytokine, IFN-γ, and its pro-inflammatory target genes, ICAM-1 and NOD2 [27].…”

Section: Introductionmentioning

confidence: 99%

“…They found the natural occurring polyamine, spermidine, was most effective in increasing PTPN2 expression and activating its phosphatase activity, as well as reducing STAT1 and STAT3 phosphorylation by IFN-γ which indicates its ability to suppress pro-inflammatory signaling cascades [27]. Spermidine treatment also decreased expression of the pro-inflammatory cytokine, IFN-γ, and its pro-inflammatory target genes, ICAM-1 and NOD2 [27]. These effects were also found to be greater in cells with the PTPN2:rs1893217-G SNP compared to wild-type cells [27].…”

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

Modulation of PTPN2/22 Function by Spermidine in CRISPR-Cas9-Edited T-Cells Associated with Crohn’s Disease and Rheumatoid Arthritis

Shaw

Qasem

Naser

2021

IJMS

View full text Add to dashboard Cite

Crohn’s Disease (CD) and Rheumatoid Arthritis (RA) share some single nucleotide polymorphisms (SNPs) in protein tyrosine phosphatase non-receptor types 2 and 22 (PTPN2/22). Recently, we reported that clinical samples from CD and RA patients associated with PTPN2:rs478582 or PTPN22:rs2476601 genotypes were linked to overactive immune response and exacerbation of inflammation. Here, we investigated in vitro the effects of these SNPs in Jurkat T-cells using CRISPR-Cas9. All cells were evaluated for PTPN22/22 loss of function and effects on cell response. We measured gene expression via RT-qPCR and cytokines by ELISA. We also measured cell proliferation using a BrdU labeling proliferation ELISA, and T-cell activation using CD-25 fluorescent immunostaining. In PTPN2 SNP-edited cells, PTPN2 expression decreased by 3.2-fold, and proliferation increased by 10.2-fold compared to control. Likewise, expression of PTPN22 decreased by 2.4-fold and proliferation increased by 8.4-fold in PTPN22 SNP-edited cells. IFN-γ and TNF-α secretions increased in both edited cell lines. CD25 expression (cell activation) was 80.32% in PTPN2 SNP-edited cells and 85.82% in PTPN22 SNP-edited cells compared to 70.48% in unedited Jurkat T-cells. Treatment of PTPN2 and PTPN22-edited cells with a maximum 20 μM spermidine restored PTPN2/22 expression and cell response including cell proliferation, activation, and cytokines secretion. Most importantly, the effect of spermidine on edited cells restored normal expression and secretion of IFN-γ and TNF-α. The data clearly demonstrated that edited SNPs in PTPN2 or PTPN22 were associated with reduced gene expression, which resulted in an increase in cell proliferation and activation and overactive immune response. The data validated our earlier observations in CD and RA clinical samples. Surprisingly, spermidine restored PTPN2/22 expression in edited Jurkat T-cells and the consequent beneficial effect on cell response and inflammation. The study supports the use of polyamines dietary supplements for management of CD and in RA patients.

show abstract

Section: Discussionmentioning

confidence: 97%

Section: Introductionmentioning

confidence: 97%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Modulation of PTPN2/22 Function by Spermidine in CRISPR-Cas9-Edited T-Cells Associated with Crohn’s Disease and Rheumatoid Arthritis

Shaw

Qasem

Naser

2021

IJMS

View full text Add to dashboard Cite

show abstract

“…TCPTP exerts an anti-inflammatory role in innate and adaptive immunity ( 113 ). As described in Section TCPTP and Immunomodulation , Tcptp knockout in systemic or specific immune cells brings about serious immune disorders.…”

Section: Therapeutic Aspects From “Tcptp and Osteoimmunology” Perspecmentioning

confidence: 99%

T Cell Protein Tyrosine Phosphatase in Osteoimmunology

et al. 2021

View full text Add to dashboard Cite

Osteoimmunology highlights the two-way communication between bone and immune cells. T cell protein tyrosine phosphatase (TCPTP), also known as protein-tyrosine phosphatase non-receptor 2 (PTPN2), is an intracellular protein tyrosine phosphatase (PTP) essential in regulating immune responses and bone metabolism via dephosphorylating target proteins. Tcptp knockout in systemic or specific immune cells can seriously damage the immune function, resulting in bone metabolism disorders. This review provided fresh insights into the potential role of TCPTP in osteoimmunology. Overall, the regulation of osteoimmunology by TCPTP is extremely complicated. TCPTP negatively regulates macrophages activation and inflammatory factors secretion to inhibit bone resorption. TCPTP regulates T lymphocytes differentiation and T lymphocytes-related cytokines signaling to maintain bone homeostasis. TCPTP is also expected to regulate bone metabolism by targeting B lymphocytes under certain time and conditions. This review offers a comprehensive update on the roles of TCPTP in osteoimmunology, which can be a promising target for the prevention and treatment of inflammatory bone loss.

show abstract

Spermidine Ameliorates Colitis via Induction of Anti-Inflammatory Macrophages and Prevention of Intestinal Dysbiosis

Niechcial

Schwarzfischer

Wawrzyniak

et al. 2023

Journal of Crohn's and Colitis

View full text Add to dashboard Cite

Background and Aims Exacerbated immune activation, intestinal dysbiosis, and a disrupted intestinal barrier are common features among inflammatory bowel disease (IBD) patients. The polyamine spermidine, which is naturally present in all living organisms, is an integral component of the human diet, and exerts beneficial effects in human diseases. Here, we investigated whether spermidine treatment ameliorates intestinal inflammation and offers therapeutic potential for IBD treatment. Methods We assessed the effect of oral spermidine administration on colitis severity in the T cell transfer colitis model in Rag2 -/- mice by analysis of endoscopy, histology, and molecular inflammation markers. The effects on the intestinal microbiome were determined by 16S sequencing of mouse feces. The impact on intestinal barrier integrity was evaluated in co-cultures of patient-derived macrophages with intestinal epithelial cells. Results Spermidine administration protected mice from intestinal inflammation in a dose-dependent manner. While T helper cell subsets remained unaffected, spermidine promoted anti-inflammatory macrophages and prevented the microbiome shift from Firmicutes and Bacteroides to Proteobacteria, maintaining a healthy gut microbiome. Consistent with spermidine as a potent activator of the anti-inflammatory molecule protein tyrosine phosphatase non-receptor type 2 (PTPN2), its colitis-protective effect was dependent on PTPN2 in intestinal epithelial cells and in myeloid cells. The loss of PTPN2 in epithelial and myeloid cells, but not in T cells, abrogated the barrier-protective, anti-inflammatory effect of spermidine and prevented the anti-inflammatory polarization of macrophages. Conclusion Spermidine reduces intestinal inflammation by promoting anti-inflammatory macrophages, maintaining a healthy microbiome, and preserving epithelial barrier integrity in a PTPN2-dependent manner.

show abstract

Presence of PTPN2 SNP rs1893217 Enhances the Anti-inflammatory Effect of Spermidine

Cited by 6 publications

References 41 publications

Modulation of PTPN2/22 Function by Spermidine in CRISPR-Cas9-Edited T-Cells Associated with Crohn’s Disease and Rheumatoid Arthritis

Modulation of PTPN2/22 Function by Spermidine in CRISPR-Cas9-Edited T-Cells Associated with Crohn’s Disease and Rheumatoid Arthritis

T Cell Protein Tyrosine Phosphatase in Osteoimmunology

Spermidine Ameliorates Colitis via Induction of Anti-Inflammatory Macrophages and Prevention of Intestinal Dysbiosis

Contact Info

Product

Resources

About