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PARP1 inactivation increases regulatory T / Th17 cell proportion in intestinal inflammation. Role of HMGB1

TitlePARP1 inactivation increases regulatory T / Th17 cell proportion in intestinal inflammation. Role of HMGB1
Publication TypeArticolo su Rivista peer-reviewed
Year of Publication2024
AuthorsVitali, Roberta, Novelli Flavia, Palone Francesca, Cucchiara S., Stronati L., and Pioli Claudio
JournalImmunology Letters
Volume270
ISSN01652478
Keywordsabsolute lymphocyte count, alarmin, animal cell, animal experiment, animal model, animal tissue, article, CD103 antigen, CD4+ T lymphocyte, Cell expansion, chemokine receptor CX3CR1, colitis, colonic lamina propria, controlled study, cytokine, dendritic cell, Dextran Sulfate, dipotassium glycyrrhizate, disease severity, enzyme inactivation, ex vivo study, Female, gene knockout, glycoprotein p 15095, glycyrrhizic acid, high mobility group B1 protein, inflammation, leukocyte count, Lymphocyte Count, mesentery lymph node, mouse, nicotinamide adenine dinucleotide adenosine diphosphate ribosyltransferase 1, nonhuman, protein expression, regulatory T lymphocyte, Spleen, T lymphocyte differentiation, Th17 cell, transcription factor FOXP3, unclassified drug, wild type
Abstract

Inflammatory bowel diseases (IBD) are chronic relapsing disorders with increasing prevalence. Knowledge gaps still limit the possibility to develop more specific and effective therapies. Using a dextran sodium sulfate colitis mouse model, we found that inflammation increased the total number and altered the frequencies of leukocytes within colon mesenteric lymph nodes (cMLNs). Although the inflammation reduced the frequency of regulatory T (Treg) cells, their absolute numbers were increased. Increased frequency of colitogenic Th17 cells was also observed. Noteworthy, untreated mice lacking Poly(ADP-ribose)-Polimerase-1 functional gene (PARP-1KO) displayed higher frequency of Treg cells and lower percentage of Th17 cells in cMLNs. In colitic PARP-1KO mice the inflammation driven expansion of the Foxp3 Treg population was more pronounced than in WT mice. Conversely, colitis increased Th17 cells to a lower extent in PARP-1KO mice compared with WT mice, resulting in a more protective Treg/Th17 cell ratio. Consequently PARP-1KO mice developed less severe colitis with reduced expression of inflammatory cytokines. In ex vivo experiments PARP-1KO and WT CD11c dendritic cells (DCs) promoted naïve CD4 T cell differentiation differently, the former sustaining more efficiently the generation of Treg cells, the latter that of Th17 cells. Addition of HMGB1 B box or of dipotassium glycyrrhizate, which sequesters extracellular HMGB1, revealed a role for this alarmin in the regulation exerted by PARP-1 on the stimulating vs. tolerogenic function of DCs during colitis. Moreover, a higher percentage of CD11c DC from PARP-1KO mice expressed CD103, a marker associated with the ability of DC to induce Treg cells, compared with WT DC. Conversely, PARP-1KO DC were including a reduced percentage of CX3CR1+ DC, described to induce Th17 cells. These findings were observed in both splenic and colon lamina propria DC. © 2024 The Author(s)

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URLhttps://www.scopus.com/inward/record.uri?eid=2-s2.0-85203087649&doi=10.1016%2fj.imlet.2024.106912&partnerID=40&md5=200a64b85e1269218d07150ba9f3c1a8
DOI10.1016/j.imlet.2024.106912
Citation KeyVitali2024