Characterization of the pathoimmunology of necrotizing enterocolitis reveals novel therapeutic opportunities

Abstract

Necrotizing enterocolitis (NEC) is a severe, currently untreatable intestinal disease that predominantly affects preterm infants and is driven by poorly characterized inflammatory pathways. Here, human and murine NEC intestines exhibit an unexpected predominance of type 3/TH17 polarization. In murine NEC, pro-inflammatory type 3 NKp46−RORγt+Tbet+ innate lymphoid cells (ILC3) are 5-fold increased, whereas ILC1 and protective NKp46+RORγt+ ILC3 are obliterated. Both species exhibit dysregulation of intestinal TLR repertoires, with TLR4 and TLR8 increased, but TLR5-7 and TLR9-12 reduced. Transgenic IL-37 effectively protects mice from intestinal injury and mortality, whilst exogenous IL-37 is only modestly efficacious. Mechanistically, IL-37 favorably modulates immune homeostasis, TLR repertoires and microbial diversity. Moreover, IL-37 and its receptor IL-1R8 are reduced in human NEC epithelia, and IL-37 is lower in blood monocytes from infants with NEC and/or lower birthweight. Our results on NEC pathomechanisms thus implicate type 3 cytokines, TLRs and IL-37 as potential targets for novel NEC therapies.

Indole-3-Carbinol–Dependent Aryl Hydrocarbon Receptor Signaling Attenuates the Inflammatory Response in Experimental Necrotizing Enterocolitis

“…Prior studies have implicated AhR activation in the production of IL-22, which has protective functions in the intestine, either by direct regulation of Il22 gene expression or through the development of CD4 1 T cells and group 3 innate lymphoid cells (ILC3s) (38,39). Further, recent work by Cho et al (40) has shown a decrease in RORgt 1 NKp46 1 ILC3s, which are prominent producers of IL-22, during murine NEC. Therefore, we next determined whether the protective effect of AhR activation with I3C treatment during NEC was IL-22 dependent.…”

Prenatal Immunity and Influences on Necrotizing Enterocolitis and Associated Neonatal Disorders

“…On the other hand, TLRs 2 and 8 have been demonstrated to be upregulated in NEC intestinal tissue from experimental animal models, as well as those samples obtained in the clinical setting from infants. However, functional pathways related to the role of these latter TLRs in pathogenesis have not been clearly defined ( 79 , 80 ). Similarly, other pattern recognition receptors including nucleotide‐binding domain and leucine‐rich repeat containing (NLR) proteins, RIG-I-like receptor and antimicrobial mediators such as mannose-binding lectin are upregulated in NEC and studies are ongoing to elucidate the associated pathways in order to identify viable therapeutic targets ( 81 – 84 ).…”

“…Accordingly, preterm naive CD4 + T cells have been found to have a higher threshold for inducing inflammation compared to adults, with impaired early Th1 differentiation including IFNγ production ( 125 ). Instead, Th2 and Th17 polarization are noted following bacterial stimulation, accompanied by low innate antiviral type 1 interferon responses ( 79 , 126 , 127 ). Similarly, IFNγ production by stimulated naive cord blood CD4 + T cells has been measured as 5 to 10-fold less relative to adult CD4 + T cells, resulting in a characterization of the preterm CD4 response as Th2 skewed ( 128 ).…”

“…Importantly, the aerosolized delivery of a novel TLR4 small molecule inhibitor was sufficient to reverse this inflammatory cascade and prevent the lung injury normally triggered by NEC in this model. Further, in NEC and other diseases with similar histopathology, Th17 skewed CD4 T cells have been shown to drive the cytokine upregulation and immune cell infiltration that constitute the mechanism of inflammation and lung injury ( 79 , 177 ). The inflammation is typically via upregulation of the chemokine CCL25, which is now known to be upregulated downstream of TLR4 activation in the lung during NEC, a phenomenon that simultaneously depletes the population of protective regulatory T cells (Tregs) present in the lung epithelium ( 176 ).…”

Stem cells and exosomes: promising candidates for necrotizing enterocolitis therapy

“…Intestinal mucosal hypoxia and impairment of the intestinal microcirculation are correlated with the development of NEC [ 5 ]. The pathoimmunological changes of NEC include deficiency in anti-inflammatory mediators and increases in pro-inflammatory mediators [ 6 , 7 ]. The anti-inflammatory cytokine interleukin (IL)-37 and its receptor, as well as protective innate lymphoid cells are deficient in NEC, while pro-inflammatory innate lymphoid cells are increased [ 7 ].…”