Siponimod Inhibits the Formation of Meningeal Ectopic Lymphoid Tissue in Experimental Autoimmune Encephalomyelitis.

BACKGROUND AND OBJECTIVES: To investigate whether the formation or retention of meningeal ectopic lymphoid tissue (mELT) can be inhibited by the sphingosine 1-phosphate receptor 1,5 modulator siponimod (BAF312) in a murine model of multiple sclerosis (MS). METHODS: A murine spontaneous chronic experimental autoimmune encephalomyelitis (EAE) model, featuring meningeal inflammatory infiltrates resembling those in MS, was used. To prevent or treat EAE, siponimod was administered daily starting either before EAE onset or at peak of disease. The extent and cellular composition of mELT, the spinal cord parenchyma, and the spleen was assessed by histology and immunohistochemistry. RESULTS: Siponimod, when applied before disease onset, ameliorated EAE. This effect was also present, although less prominent, when treatment started at peak of disease. Treatment with siponimod resulted in a strong reduction of the extent of mELT in both treatment paradigms. Both B and T cells were diminished in the meningeal compartment. DISCUSSION: Beneficial effects on the disease course correlated with a reduction in mELT, suggesting that inhibition of mELT may be an additional mechanism of action of siponimod in the treatment of EAE. Further studies are needed to establish causality and confirm this observation in MS.

Suppression of plasmacytoid dendritic cell migration to colonic isolated lymphoid follicles abrogates the development of colitis.

BACKGROUND: Dendritic cells (DCs) play a pivotal role in maintaining immunological homeostasis by orchestrating innate and adaptive immune responses via migration to inflamed sites and the lymph nodes (LNs). Plasmacytoid DCs (pDCs) have been reported to accumulate in the colon of inflammatory bowel disease (IBD) patients and dextran sulfate sodium (DSS)-induced colitis mice. However, the role of pDCs in the progression of colonic inflammation remains unclear. METHODS: 80 compounds in natural medicines were searched for inhibitors of pDC migration using bone marrow-derived pDCs (BMpDCs) and conventional DCs (BMcDCs). BALB/c mice were given 3% DSS in the drinking water to induce acute colitis. Compounds, which specifically inhibited pDC migration, were administrated into DSS-induced colitis mice. FINDINGS: Astragaloside IV (As-IV) and oxymatrine (Oxy) suppressed BMpDC migration but not BMcDC migration. In DSS-induced colitis mice, the number of pDCs was markedly increased in the colonic lamina propria (LP), and the expression of CCL21 was obviously observed in colonic isolated lymphoid follicles (ILFs). As-IV and Oxy reduced symptoms of colitis and the accumulation of pDCs in colonic ILFs but not in the colonic LP. Moreover, in a BMpDC adoptive transfer model, BMpDC migration to colonic ILFs was significantly decreased by treatment with As-IV or Oxy. INTERPRETATION: pDCs accumulated in the colon of colitis mice, and As-IV and Oxy ameliorated colitis by suppressing pDC migration to colonic ILFs. Accordingly, the selective inhibition of pDC migration may be a potential therapeutic approach for treating colonic inflammatory diseases.

Prostaglandin-endoperoxide synthase 2 (cyclooxygenase-2), a complex target for colorectal cancer prevention and therapy.

A plentiful literature has linked colorectal cancer (CRC) to inflammation and prostaglandin-endoperoxide synthase (PTGS)2 expression. Accordingly, several nonsteroidal antiinflammatory drugs (NSAIDs) have been tested often successfully in CRC chemoprevention despite their different ability to specifically target PTGS2 and the low or null expression of PTGS2 in early colon adenomas. Some observational studies showed an increased survival for patients with CRC assuming NSAIDs after diagnosis, but no clinical trial has yet demonstrated the efficacy of NSAIDs against established CRC, where PTGS2 is expressed at high levels. The major limits for the application of NSAIDs, or specific PTGS2 inhibitors, as adjuvant drugs in CRC are (1) a frequent confusion about the physiological role of PTGS1 and PTGS2, reflecting in CRC pathology and therapy; (2) the presence of unavoidable side effects linked to the intrinsic function of these enzymes; (3) the need of established criteria and markers for patient selection; and (4) the evaluation of the immunomodulatory potential of PTGS2 inhibitors as possible adjuvants for immunotherapy. This review has been written to rediscover the multifaceted potential of PTGS2 targeting, hoping it could act as a starting point for a new and more aware application of NSAIDs against CRC.