Introduction: Necrotizing enterocolitis (NEC) is sometimes dubbed the spectre of neonatal intensive care units (NICUs), as its onset is insidiously non-specific and once NEC becomes manifest, the damage inflicted on the premature baby’s intestine and other organs is often disastrous. It remains unknown which participants of the immune system initiate the cascade of events that lead to NEC; consequently, no specific therapy exists. We hypothesize that an immature and inappropriate inflammatory response towards bacterial colonization and/or food components plays a pivotal role in the initiation and perpetuation of NEC. Hence, we investigated the therapeutic potential of the anti-inflammatory cytokine interleukin-37 (IL-37) in a murine model of NEC.

Methods: Newborn C57BL6J mice transgenic for IL-37 (IL-37tg) and wild-type (WT) controls (n=8 for both) were collected and separated from dams at birth. Mice were formula-fed every 3hrs using the Yajima style Hoshiba nipple and subjected to asphyxia (100% nitrogen gas for 45s) followed by cold stress (4°C, 5mins) twice daily to induce NEC. At the experimental endpoint (72hrs), all pups were culled and intestinal samples collected. Littermates were dam-fed and kept as controls (n=16).

Results: On a 0-3 scale (no to severe pathology), clinical scores were 1.8 (WT) vs 1.2 (IL-37tg) for ileus, 0.9 vs 0.1 for hematochezia and 1.5 vs 0.6 for diarrhea. Tissue histological injury scores assessing epithelial vacuolation and mucosal disintegration were 1.8 (WT) vs 0.8 (IL-37tg) in the duodenum, 1.4 vs 0.6 in the jejunum and 1.4 vs 0.8 in the ileum. This marked reduction of NEC severity in IL-37tg mice was associated with a decrease in IL-1β.

Conclusion: Our results demonstrate that IL-37 protects newborn mice against NEC, indicating that excessive inflammation contributes to disease progression. Blocking this inappropriate inflammatory response may represent a promising approach to improve the outlook of babies suffering from this devastating disease.