Sphk2 deletion is involved in structural abnormalities and Th17 response but does not aggravate colon inflammation induced by sub-chronic stress

• Published in: Scientific reports Vol. 12; no. 1; p. 4073
• Main Authors: Martín-Hernández, David, Gutiérrez, Irene L., González-Prieto, Marta, MacDowell, Karina S., Robledo-Montaña, Javier, Tendilla-Beltrán, Hiram, Calleja-Rodríguez, Natalia, Bris, Álvaro G., Ulecia-Morón, Cristina, Moreno, Beatriz, Caso, Javier R., García-Bueno, Borja, Rodrigues-Mascarenhas, Sandra, Marín-Jiménez, Ignacio, Leza, Juan Carlos, Menchén, Luis
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 08.03.2022; Nature Publishing Group; Nature Portfolio
• Subjects: 631/250/256; 631/250/347; 631/337; 692/308/2778; 692/4020/1503/257; Animals; Antigens; Biodegradation; CD45 antigen; Colitis - genetics; Colitis - immunology; Colitis - metabolism; Colon; Cytokines; Cytokines - immunology; Helper cells; Humanities and Social Sciences; Immune response; Immunoglobulin A; Immunoglobulin M; Immunosuppressive agents; Inflammatory bowel diseases; Inflammatory Bowel Diseases - genetics; Inflammatory Bowel Diseases - immunology; Inflammatory Bowel Diseases - metabolism; Intestine; Kinases; Lymphocytes; Lymphocytes B; Lymphocytes T; Lysophospholipids - metabolism; Mice; Mice, Knockout; multidisciplinary; Permeability; Phosphotransferases (Alcohol Group Acceptor) - deficiency; Phosphotransferases (Alcohol Group Acceptor) - immunology; Phosphotransferases (Alcohol Group Acceptor) - metabolism; Plasmacytosis; Science; Science (multidisciplinary); Sphingosine - metabolism; Sphingosine 1-phosphate; Sphingosine kinase; Stress, Psychological - immunology; Stress, Psychological - metabolism; Th17 Cells - immunology; Th17 Cells - metabolism; TLR4 protein; Toll-like receptors
• ISSN: 2045-2322; 2045-2322
• DOI: 10.1038/s41598-022-08011-8

The chronic inflammatory process that characterizes inflammatory bowel diseases (IBD) is mainly driven by T-cell response to microbial and environmental antigens. Psychological stress is a potential trigger of clinical flares of IBD, and sphingosine-1-phosphate (S1P) is involved in T-cell recruitment. Hence, stress impact and the absence of sphingosine kinase 2 (Sphk2), an enzyme of S1P metabolism, were evaluated in the colon of mice after sub-chronic stress exposure. Here, we show that sub-chronic stress increased S1P in the mouse colon, possibly due to a decrease in its degradation enzymes and Sphk2. S1P accumulation could lead to inflammation and immune dysregulation reflected by upregulation of toll-like receptor 4 (TLR4) pathway, inhibition of anti-inflammatory mechanisms, cytokine-expression profile towards a T-helper lymphocyte 17 (Th17) polarization, plasmacytosis, decrease in IgA+ lymphoid lineage cells (CD45+)/B cells/plasmablasts, and increase in IgM+ B cells. Stress also enhanced intestinal permeability. Sphk2 knockout mice presented a cytokine-expression profile towards a boosted Th17 response, lower expression of claudin 3,4,7,8, and structural abnormalities in the colon. Intestinal pathophysiology should consider stress and S1P as modulators of the immune response. S1P-based drugs, including Sphk2 potentiation, represent a promising approach to treat IBD.