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

David Martín-Hernández,Álvaro G Bris,Marta González-Prieto,Natalia Calleja-Rodríguez,Ignacio Marín-Jiménez,Irene L Gutiérrez,Beatriz Moreno,Juan Carlos Leza,Cristina Ulecia-Morón,Javier Robledo-Montaña,Karina S Macdowell,Hiram Tendilla-Beltrán,Javier R Caso,Sandra Rodrigues-Mascarenhas,Luis Menchén,Borja García-Bueno

doi:10.1038/s41598-022-08011-8

Abstract

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.

Highlights

The chronic inflammatory process that characterizes inflammatory bowel diseases (IBD) is mainly driven by T-cell response to microbial and environmental antigens
S1P, its synthesis (Sphk[1], sphingosine kinase 2 (Sphk2)), and degradation (SGPL1, SGPP1, SGPP2) enzymes were measured after stress exposure in wild-type (WT) and Sphk2−/− mice
No effects compromising the normal immune system activity were recorded in Sphk2−/− mice beyond mild anaphylaxis with a fast recovery that, a priori, does not impact IBD17

Summary

Introduction

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. 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. We show that sub-chronic stress increased S1P in the mouse colon, possibly due to a decrease in its degradation enzymes and Sphk[2]. Intestinal pathophysiology should consider stress and S1P as modulators of the immune response. As a result of altered immune response to environmental antigens, including microbes, chronic inflammation represents the main feature of IBD. Sphingosine-1-phosphate (S1P) emerges as a promising pathway to modulate intestinal inflammatory processes, as demonstrated by encouraging results of phase II clinical trials targeting S1P receptor subtypes 1 and 5 (S1PR1/5)[6]. Psychological stress can modulate S1P signaling, and its receptors have been proposed as pharmacological targets due to their capacity to control n euroinflammation[10]

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Conclusion