Slco2a1 deficiency exacerbates experimental colitis via inflammasome activation in macrophages: a possible mechanism of chronic enteropathy associated with SLCO2A1 gene

Abstract

Loss-of-function mutations in the solute carrier organic anion transporter family, member 2a1 gene (SLCO2A1), which encodes a prostaglandin (PG) transporter, have been identified as causes of chronic nonspecific multiple ulcers in the small intestine; however, the underlying mechanisms have not been revealed. We, therefore, evaluated the effects of systemic knockout of Slco2a1 (Slco2a1 −/−) and conditional knockout in intestinal epithelial cells (Slco2a1 ΔIEC) and macrophages (Slco2a1 ΔMP) in mice with dextran sodium sulphate (DSS)-induced acute colitis. Slco2a −/− mice were more susceptible to DSS-induced colitis than wild-type (WT) mice, but did not spontaneously develop enteritis or colitis. The nucleotide-binding domain, leucine-rich repeats containing family, pyrin domain-containing-3 (NLRP3) inflammasome was more strongly upregulated in colon tissues of Slco2a −/− mice administered DSS and in macrophages isolated from Slco2a1 −/− mice than in the WT counterparts. Slco2a1 ΔMP , but not Slco2a1 ΔIEC mice, were more susceptible to DSS-induced colitis than WT mice, partly phenocopying Slco2a −/− mice. Concentrations of PGE 2 in colon tissues and macrophages from Slco2a1 −/− mice were significantly higher than those of WT mice. Blockade of inflammasome activation suppressed the exacerbation of colitis. These results indicated that Slco2a1-deficiency increases the PGE 2 concentration, resulting in NLRP3 inflammasome activation in macrophages, thus exacerbating intestinal inflammation. Prostaglandin (PG) E 2 is the most physiologically abundant eicosanoid biosynthesized from arachidonic acid by cyclooxygenase (COX). PGE 2 has important roles in maintaining gut mucosal homeostasis 1,2 , but also is an essential mediator of the immune response and inflammation in various inflammatory diseases 3. Indeed, small intestinal ulcers can be induced by nonsteroidal anti-inflammatory drugs (NSAIDs) treatment through suppressing PGE 2 synthesis by inhibition of COX. PGE 2 is exported to the extracellular microenvironment by multiple drug resistance-associated protein 4 (MRP4/ABCC4) 4 and exerts its effects by binding to a family of G protein-coupled receptors consisting of four subtypes: EP1, EP2, EP3, and EP4 5. Prostaglandin transporter (PGT), encoded by the solute carrier organic anion transporter family, member 2a1 gene (SLCO2A1) mediates cellular uptake of PGE 2 6,7. PGE 2 is oxidized intracellularly by 15-ketoprostaglandin dehydrogenase (15-PGDH; encoded by HPGD) 8,9. Thus, PGT plays an important role in PGE 2 metabolism. Umeno et al. recently reported that chronic enteropathy, which

Non‐steroidal anti‐inflammatory drugs, prostaglandins, and COVID‐19

“…(Mortimer, Moreau, Mac-Donald, & Chadee, 2016;Sokolowska et al, 2015). However, other authors report positive effects of PGE 2 upon NLRP3 inflammasome activation and IL-1β production in macrophages and monocytes under various stimuli (Nakata et al, 2020;Sheppe et al, 2018;Zasłona et al, 2017). Taken together, these findings indicate contextdependent modulation of NLRP3 inflammasome activation by PGE 2 .…”

“…PGE 2 was reported to inhibit NLRP3 inflammasome activation in macrophages through EP4 receptors, and blockade of COX‐2 or EP4 receptors resulted in increased NLRP3 inflammasome activation (Mortimer, Moreau, MacDonald, & Chadee, 2016; Sokolowska et al, 2015). However, other authors report positive effects of PGE 2 upon NLRP3 inflammasome activation and IL‐1β production in macrophages and monocytes under various stimuli (Nakata et al, 2020; Sheppe et al, 2018; Zasłona et al, 2017). Taken together, these findings indicate context‐dependent modulation of NLRP3 inflammasome activation by PGE 2 .…”

A novel mutation in the SLCO2A1 gene, encoding a prostaglandin transporter, induces chronic enteropathy

“…This might be due to differences in the PGE 2 metabolic activities between mice and humans. Further, although recent studies have shown that SLCO2A1 function is lost in patients with CEAS, Slco2a1- deficient mice do not spontaneously develop enteritis [ 28 ]. This might be because Slco2a1 / SLCO2A1 has different functions in mice and humans.…”

Effects of Milk-Derived Extracellular Vesicles on the Colonic Transcriptome and Proteome in Murine Model

“…GSTT1 is found to alleviate colitis by the IL-22 dependent pathway [ 43 ]. SlCO2A1 deficiency is identified to deteriorate intestinal inflammation by activating the NLRP3 inflammasome in macrophages [ 44 ]. For the reasons above, the up-regulated CYP1A1 , SLC6A4 , SLC6A8 , PHLPP2 , ANO1 , NR1D1 , CPA6 , GLP-2R , GSTT1 and SlCO2A1 in mEV−fed mice indicated that mEVs facilitated the expression of genes that had low expression in colitis, and hence ameliorated colitis.…”