UniPR1331: Small Eph/Ephrin Antagonist Beneficial in Intestinal Inflammation by Interfering with Type-B Signaling

• Published in: Pharmaceuticals (Basel, Switzerland) Vol. 14; no. 6; p. 502
• Main Authors: Giorgio, Carmine, Allodi, Marika, Palese, Simone, Grandi, Andrea, Tognolini, Massimiliano, Castelli, Riccardo, Lodola, Alessio, Flammini, Lisa, Cantoni, Anna Maria, Barocelli, Elisabetta, Bertoni, Simona
• Format: Journal Article
• Language: English
• Published: Basel MDPI AG 24.05.2021; MDPI
• Subjects: Colon; Cytokines; Drug dosages; EphA2; ephrin-A1-Fc; Gene expression; Inflammation; Inflammatory bowel disease; Investigations; Kinases; Lymphocytes; Neutrophils; Proteins; splenocytes; sulfasalazine; TNBS-induced colitis
• ISSN: 1424-8247; 1424-8247
• DOI: 10.3390/ph14060502

Eph receptors, comprising A and B classes, interact with cell-bound ephrins generating bidirectional signaling. Although mainly related to carcinogenesis and organogenesis, the role of Eph/ephrin system in inflammation is growingly acknowledged. Recently, we showed that EphA/ephrin-A proteins can modulate the acute inflammatory responses induced by mesenteric ischemia/reperfusion, while beneficial effects were granted by EphB4, acting as EphB/ephrin-B antagonist, in a murine model of Crohn’s disease (CD). Accordingly, we now aim to evaluate the effects of UniPR1331, a pan-Eph/ephrin antagonist, in TNBS-induced colitis and to ascertain whether UniPR1331 effects can be attributed to A- or B-type signaling interference. The potential anti-inflammatory action of UniPR1331 was compared to those of the recombinant proteins EphA2, a purported EphA/ephrin-A antagonist, and of ephrin-A1-Fc and EphA2-Fc, supposedly activating forward and reverse EphA/ephrin-A signaling, in murine TNBS-induced colitis and in stimulated cultured mononuclear splenocytes. UniPR1331 antagonized the inflammatory responses both in vivo, mimicking EphB4 protection, and in vitro; EphA/ephrin-A proteins were inactive or only weakly effective. Our findings represent a further proof-of-concept that blockade of EphB/ephrin-B signaling is a promising pharmacological strategy for CD management and highlight UniPR1331 as a novel drug candidate, seemingly working through the modulation of immune responses.