Toll Like Receptor 4 Mediated Lymphocyte Imbalance Induces Nec-Induced Lung Injury

Abstract

Necrotizing enterocolitis (NEC) is the leading cause of death from gastrointestinal disease in premature infants, and is associated with the development of severe lung inflammation. The pathogenesis of NEC-induced lung injury remains unknown, yet infiltrating immune cells may play a role. In support of this possibility, we now show that NEC in mice and humans was associated with the development of profound lung injury that was characterized by an influx of Th17 cells and a reduction in Tregs. Importantly, the adoptive transfer of CD4 T cells isolated from lungs of mice with NEC into the lungs of immune incompetent mice (Rag1 mice) induced profound inflammation in the lung, while the depletion of Tregs exacerbated NEC induced lung injury, demonstrating that imbalance of Th17/Treg in the lung is required for the induction of injury. In seeking to define the mechanisms involved, the selective deletion of TLR4 from the Sftpc1 pulmonary epithelial cells reversed lung injury, while TLR4 activation induced the Th17 recruiting chemokine (C-C motif) ligand 25 (CCL25) in the lungs of mice with NEC. Strikingly, the aerosolized inhibition of both CCL25 and TLR4 and the administration of all trans retinoic acid restored Tregs attenuated NEC-induced lung injury. In summary, we show that TLR4 activation in Surfactant protein C-1 (Sftpc1) cells disrupts the Treg/Th17 balance in the lung via CCL25 leading to lung injury after NEC and reveal that inhibition of TLR4 and stabilization of Th17/Treg balance in the neonatal lung may prevent this devastating complication of NEC.

A Dynamic Variation of Pulmonary ACE2 Is Required to Modulate Neutrophilic Inflammation in Response to Pseudomonas aeruginosa Lung Infection in Mice

“…It has been reported that IL-17 is critical in mediating pulmonary neutrophil infiltration, whereas the lungs encountered infectious insults (40)(41)(42)(43)(44). Our previous studies in necrotizing enterocolitisinduced lung injury also indicated that IL-17 is critical in neutrophilic lung inflammation (45). Thus, we hypothesized that IL-17-mediated neutrophil influx is, at least in part, the underlying mechanism by which ACE2 modulates neutrophilic inflammation in bacterial lung infection.…”

A Novel Role for Necroptosis in the Pathogenesis of Necrotizing Enterocolitis

“…Although intestinal damage is the most significant contributor to illness in patients with NEC, these children also experience damage to peripheral organs, including the lungs and brain. 30,65,66 Remote organ injury in neonates with NEC occurs in part through the release of TLR4 ligands from the damaged gut, including high mobility group box 1 (HMGB1), which is released from dying intestine into the circulation, where it causes injury to both the lung and brain, through pathways that are incompletely understood. 30,67 It is noteworthy that HMGB1 also has been shown to form a complex with bacterial lipids during inflammation, which can trigger RIPK3-dependent immune responses, 68 suggesting the possibility that HMGB1 release also may induce necroptosis in these other organs.…”

Dysregulated Mucosal Immunity and Associated Pathogeneses in Preterm Neonates

“…NEC-induced lung injury is particularly severe as compared to the lung injury that develops in premature infants who do not develop NEC. We have shown that TLR4 expression on the lung epithelium is required for the recruitment of proinflammatory neutrophils into the lung through the upregulation of CCL25 (50,51), and that strategies to either inhibit TLR4 via the administration of aerosolized inhibitors, or through genetic deletion, can serve as novel lung protective strategies in the setting of NEC (50).…”