Argininosuccinate lyase in enterocytes protects from development of necrotizing enterocolitis

M. H. Premkumar, G. Sule, S. C. Nagamani, S. Chakkalakal, A. Nordin, M. Jain, M. Z. Ruan, T. Bertin, B. Dawson, J. Zhang, D. Schady, N. S. Bryan, P. M. Campeau, A. Erez, B. Lee

Necrotizing enterocolitis (NEC), the most common neonatal gastrointestinal emergency, results in significant mortality and morbidity, yet its pathogenesis remains unclear. Argininosuccinate lyase (ASL) is the only enzyme in mammals that is capable of synthesizing arginine. Arginine has several homeostatic roles in the gut and its deficiency has been associated with NEC. Since enterocytes are the primary sites of arginine synthesis in neonatal mammals, we evaluated the consequences of disruption of arginine synthesis in the enterocytes on the pathogenesis of NEC. We devised a novel approach to study the role of enterocyte-derived ASL in NEC by generating and characterizing a mouse model with enterocyte-specific deletion of Asl (Asl (flox/flox); VillinCre(tg/+) or CKO). We hypothesized that the presence of ASL in a cell-specific manner in the enterocytes is protective in the pathogenesis of NEC. Loss of ASL in enterocytes resulted in an increased incidence of NEC that was associated with a pro-inflammatory state and increased enterocyte apoptosis. Knockdown of ASL in intestinal epithelial cell lines resulted in decreased migration in response to lipopolysaccharide (LPS). Our results show that the enterocyte-derived ASL has a protective role in the NEC.