A Novel Therapeutic Target in Inflammatory Uveitis: Transglutaminase 2 Inhibitor

Abstract

PurposeOur goal was to investigate the effects of inhibition of transglutaminase 2 (TGase 2) on endotoxin-induced uveitis (EIU)MethodsEIU was induced in female Lewis rats by single footpad injections of 200 µg of lipopolysaccharide (LPS). TGase 2 inhibitors were administered intraperitoneally 30 minutes before and at the time of LPS administration. Rats were sacrificed 24 hours after injection, and the effects of the TGase 2 inhibitors were evaluated by the number of intraocular inflammatory cells present on histologic sections and by measuring the TGase 2 activity and TGase products in the aqueous humor (AqH). TGase 2 substrates were also assayed in AqH from uveitis patients.ResultsClinical indications of EIU, the number of cells present on histologic sections, and TGase 2 activity in AqH increased in a time-dependent manner, peaking 24 hours after LPS injection. Inflammation in EIU was significantly reversed by treatment with TGase inhibitors. A 23-kDa cross-linked TGase substrate was identified in the AqH from EIU rats and uveitis patients. MALDI-TOF analysis showed that this substrate in uveitis patients was human Ig kappa chain C region.ConclusionsTGase 2 activity and its catalytic product were increased in the AqH of EIU rats. TGase 2 inhibition attenuated the degree of inflammation in EIU. Safe and stable TGase inhibitors may have great potential for the treatment of inflammatory uveitis.

Transglutaminase 2 cross-linking activity is linked to invadopodia formation and cartilage breakdown in arthritis

“…Our results indicate that TG2, mostly through its TGase activity, plays a critical role in experimental arthritis by promoting the breakdown of cartilage components by synovial cells. Inhibitors of the TGase activity of TG2 in rat models have shown efficacy in reversing the inflammation and fibrosis associated with chronic kidney diseases and inflammatory uveitis without apparent toxicity or side effects [66,67]. These observations suggest that TGase inhibition may provide a promising approach for the development of therapies aimed at stopping the process of cartilage degradation in arthritis.…”

Infection‐driven activation of transglutaminase 2 boosts glucose uptake and hexosamine biosynthesis in epithelial cells

“…Sixty‐two proteins were found to be significantly enriched in the infected cell lysates grown in the presence of BP (Appendix Table S1). Fibronectin, galectin 3, RhoA, 40S ribosomal protein SA, immunoglobulin κ chain C region, and hemoglobin beta were already identified as TG2 substrates (Pincus & Waelsch, ; Mehul et al , ; Orrù et al , ; Guilluy et al , ; Nelea et al , ; Sohn et al , ). BAG2 and several other mitochondrial proteins were also enriched in the samples prepared in the presence of BP, in agreement with TG2 being present and active in this compartment (Altuntas et al , ).…”

Transglutaminase 2 in human diseases

“…As a result, a marked reduction in ICAM-1 expression and lung neutrophil sequestration was observed in TG2 knockout compared to wild type mice after intraperitoneal LPS challenge [ 152 ]. Accordingly, transglutaminase inhibitors ameliorate endotoxin-induced uveitis [ 153 ] and trapping TG2 by a fusion protein attenuates corneal inflammation and neovascularization [ 154 ].…”