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P033 DSS-induced colitis is attenuated in sigma-1 receptor knockout mice

Lόpez-Estévez S.*1, Aguilera M.1, Gris G.2, de la Puente B.2, Codony X.2, Zamanillo D.2, Martínez V.1

1Universitat Autònoma de Barcelona, Cell Biology, Physiology and Immumology, Bellaterra, Spain 2Esteve, Department of Pharmacology, Drug Discovery & Preclinical Development, Barcelona, Spain

Background

Sigma-1 receptors (σ1Rs) have immunomodulatory properties and have been shown to modulate gene expression of several proteins related to inflammation. Indeed, σ1R modulation has been suggested to be potentially useful in pathologies where pro-inflammatory cytokines are involved. Here we assessed the potential implication of σ1Rs on colitis using a murine model knockout for σ1Rs.

Methods

Adult CD-1 male wild type (WT) and σ1R knockout mice (σ1R KO) were used. Colitis was induced by exposure to a 3% solution of dextran sodium sulfate (DSS) during a 5-day period, followed by a 3-day recovery. Body weight and clinical signs were assessed on a daily basis. At termination, colonic inflammation was assessed macro and microscopically (Stress 2008,11:348–62). Colonic expression of pro- (Interferon -INF-, IL-1, IL-6, IL-18 and IL-12p40) and anti-inflammatory cytokines (IL-10) was also determined (RT-qPCR).

Results

During colitis induction, body weight loss and clinical signs were attenuated in σ1R KO vs. WT animals. At necropsy, colonic inflammatory score, changes in colon length and relative weight and colonic histopathological scores were also attenuated in σ1R KO mice (Table 1). Improvement in histopathological scores was due mainly to a reduction in submucosal edema. Basal expression of cytokines was similar in WT and σ1R KO mice, except for IL-12p40 which was up-regulated by 4-fold in σ1R KO mice (p<0.05 vs. WT). During colitis, INF, IL-1 and IL-6 were up-regulated in WT mice (all p<0.05 vs. non-inflamed WT), while only minor expression changes were observed in KO animals (all p>0.05 vs. non-inflamed σ1R KO mice). IL-12p40 showed a selective down-regulation in colitic σ1R KO mice while IL-18 showed minor, non-significant, changes. Regardless the phenotype considered, no changes in IL-10 expression were detected. Expression of σ1Rs was detected in the colon of WT mice, but not in KO animals. In WT mice, σ1R expression was reduced by 28% (p<0.05) during colitis.

Table 1

Macrocopic score (0–12)Microscopic score (0–12)Colon length (cm)Colon relative weight (mg/cm)
WTWater0±01.29±0.2211.09±0.2626.45±0.75
WTDSS4.18±1.05*7.73±0.62*9.09±0.44*53.82±3.30*
KOWater0±01.33±0.2411.22±0.3325.60±1.03
KODSS0.08±0.084.77±0.51*#10.83±0.28#32.50±1.69*#

Data are mean ± SEM, n=12–13 animals per group. *p<0.05 vs. respective water-treated group; #p<0.05 vs. WT-DSS group.

Conclusion

Lack of functional σ1Rs resulted in an attenuated inflammatory and immune response in the DDS-induced colitis model in mice. These results indicate that σ1Rs are implicated in the modulation of intestinal inflammation. Antagonism of σ1Rs might represent a pharmacological approach for the treatment of intestinal inflammation.