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Additionally, to examine the effect of pulpitis with necrosis (PWN) on the number and activation of peripheral and bone marrow (BM) neutrophils, as well as spleen lymphocytes, in a mouse model of pulpitis.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methodology<\/jats:title>\n                    <jats:p>\n                      The material comprised 20 permanent teeth, with or without caries, which were classified into three histological categories based on the distribution of inflammatory cells and the presence or absence of necrosis: (i) healthy pulp (HP), (ii) pulpitis without necrosis (PWON), and (iii) PWN. The levels of the four regulated cell death (RCD) pathways were detected by immunohistochemical and immunofluorescent staining with specific markers: apoptosis (caspase\u20108, cleaved caspase\u20103), pyroptosis (cleaved caspase\u20101, membrane\u2010binding gasdermin D), necroptosis (receptor\u2010interacting kinase 3, phosphorylated MLKL), and NETosis (myeloperoxidase, citrullinated histone H3). Acute pulpitis was induced in C57BL\/6J mice via pulp exposure, and the mice were divided into four groups: (i) control (no tooth preparation,\n                      <jats:italic>n<\/jats:italic>\n                      \u2009=\u20096), (ii) Day 1 (sacrificed at 1\u2009day after pulp exposure,\n                      <jats:italic>n<\/jats:italic>\n                      \u2009=\u20093), (iii) Day 3 (\n                      <jats:italic>n<\/jats:italic>\n                      \u2009=\u20093), and (iv) Day 5 (\n                      <jats:italic>n<\/jats:italic>\n                      \u2009=\u20097). The control and Day 5 groups were used for further immunofluorescent analysis to assess the levels of RCD and flow cytometry to monitor the changes in peripheral and BM neutrophils, as well as spleen lymphocytes. Human dental pulp stem cells (hDPSCs) were isolated and cultured from extracted healthy third molars. Apoptosis and necroptosis in hDPSCs were induced by staurosporine, whilst pyroptosis was induced by lipopolysaccharide and nigericin. One\u2010way analysis of variance (ANOVA) with Tukey's test, Welch's ANOVA with Tamhane's test, and Student's\n                      <jats:italic>t<\/jats:italic>\n                      \u2010tests were used to compare immunohistochemical labelling and flow cytometric data amongst groups (\n                      <jats:italic>p<\/jats:italic>\n                      \u2009&lt;\u2009.05).\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      The pulpal tissue of PWN can be divided into the abscess core (PWN\u2010AC) and fibrous tissue (PWN\u2010FT). The ratio of total necrotic cells (TUNEL\u2010positive) in PWN\u2010AC was significantly higher than in PWN\u2010FT and PWON (both\n                      <jats:italic>p<\/jats:italic>\n                      \u2009&lt;\u2009.01). Compared with HP, the expression levels of markers for apoptosis and pyroptosis were increased in PWON, whilst the expression levels of markers for apoptosis, pyroptosis, and NETosis were elevated in PWN, primarily detected in PWN\u2010AC. Interestingly, myeloperoxidase (MPO) was exclusively observed in PWN\u2010AC, with minimal detection in PWN\u2010FT and PWON. Additionally, the frequency of MPO\n                      <jats:sup>+<\/jats:sup>\n                      cells was significantly higher than that of MB\u2010GSDMD\n                      <jats:sup>+<\/jats:sup>\n                      cells and Cl\u2010cas3\n                      <jats:sup>+<\/jats:sup>\n                      cells in PWN\u2010AC (both\n                      <jats:italic>p<\/jats:italic>\n                      \u2009&lt;\u2009.01). Histological observation and TUNEL staining showed abundant necrotic cells in mouse pulpal tissue after pulp exposure, indicating a simulation of human PWN. In mouse pulpitis tissue, markers of apoptosis, pyroptosis, and NETosis were detected. In\u00a0vitro, various cell deaths including apoptosis, pyroptosis, and necroptosis were also triggered in hDPSCs under various cell death treatments. Furthermore, in terms of systemic changes, pulp exposure\u2010induced pulpitis could increase the number (\n                      <jats:italic>p<\/jats:italic>\n                      \u2009&lt;\u2009.05) and cellular activity (\n                      <jats:italic>p<\/jats:italic>\n                      \u2009&lt;\u2009.01) of neutrophils from BM in a mouse model. No significant changes in peripheral blood neutrophils, spleen T cells, B cells, or the CD4\/CD8 ratio were detected between the control and pulpitis mice.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>Our findings uncover distinct patterns of mixed cell death at different histological stages of human pulpitis and the impact of pulpitis on the number and activity of BM neutrophils. Notably, NETosis occurs specifically and predominates in the abscess area of pulpitis, suggesting a potential effect of neutrophil extracellular traps (NETs) on pulpitis progression and NETs\u2010targeted diagnostic strategy may play a role in decision making for vital pulp therapy.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1111\/iej.14145","type":"journal-article","created":{"date-parts":[[2024,9,11]],"date-time":"2024-09-11T01:34:21Z","timestamp":1726018461000},"page":"111-127","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":14,"title":["Multiple cell death modalities and immune response in pulpitis"],"prefix":"10.1111","volume":"58","author":[{"given":"Ben","family":"Wang","sequence":"first","affiliation":[{"name":"Hospital of Stomatology, Guanghua School of Stomatology Sun Yat\u2010sen University  Guangzhou P.R. China"},{"name":"South China Center of Craniofacial Stem Cell Research  Guangzhou P.R. 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