The immunological landscape in necrotising enterocolitis

Abstract

Necrotising enterocolitis (NEC) is an uncommon, but devastating intestinal inflammatory disease that predominantly affects preterm infants. NEC is sometimes dubbed the spectre of neonatal intensive care units, as its onset is insidiously non-specific, and once the disease manifests, the damage inflicted on the baby's intestine is already disastrous. Subsequent sepsis and multi-organ failure entail a mortality of up to 65%. Development of effective treatments for NEC has stagnated, largely because of our lack of understanding of NEC pathogenesis. It is clear, however, that NEC is driven by a profoundly dysregulated immune system. NEC is associated with local increases in pro-inflammatory mediators, e.g. Toll-like receptor (TLR) 4, nuclear factor-κB, tumour necrosis factor, platelet-activating factor (PAF), interleukin (IL)-18, interferon-gamma, IL-6, IL-8 and IL-1β. Deficiencies in counter-regulatory mechanisms, including IL-1 receptor antagonist (IL-1Ra), TLR9, PAF-acetylhydrolase, transforming growth factor beta (TGF-β)1&2, IL-10 and regulatory T cells likely facilitate a pro-inflammatory milieu in the NEC-afflicted intestine. There is insufficient evidence to conclude a predominance of an adaptive Th1-, Th2- or Th17-response in the disease. Our understanding of the accompanying regulation of systemic immunity remains poor; however, IL-1Ra, IL-6, IL-8 and TGF-β1 show promise as biomarkers. Here, we chart the emerging immunological landscape that underpins NEC by reviewing the involvement and potential clinical implications of innate and adaptive immune mediators and their regulation in NEC.

Figure 1.

Modified Bell's staging criteria for necrotising enterocolitis, adapted from (Ref. 10).

Figure 2.

Model of NEC pathogenesis in the preterm intestine. (a) Multiple factors are involved in the precipitation of NEC, including dysbiosis, formula feeding, and ischaemic/hypoxic assaults. (b) Inappropriate increases in abundance of, and signalling by, pro-inflammatory pattern recognition receptors (PRRs) such as TLR4 contribute to the initiation of a cascade that involves (c) antigen processing by antigen-presenting cells such as dendritic cells (DCs) and (d) activation of other immune cells such as T cells, monocytes, macrophages and regulatory T cells (Tregs), leading to (e) an inappropriate and excessive increase of pro-inflammatory cytokines, chemokines and transcription factors. (f) A deficiency in counter-regulatory mediators contributes to this pro-inflammatory milieu to self-perpetuate and spiral out of control – (g) a vicious cycle is formed. (h) Inflammation-, ischaemia/reperfusion- and hypoxia-associated injury compromises the endothelial integrity of the local blood vessels, which also feeds the vicious cycle. (i) Necrotic cell death of the intestinal epithelium ensues, further exacerbating tissue injury and inflammation. (j) In line with the clinical stages (see Fig. 1), NEC severity can range from mild intestinal injury to segmental or even complete destruction of the intestinal epithelium. (k) Disintegration of the intestinal epithelium compromises its barrier functions, ultimately leading to rampant bacterial translocation into the lamina propria and the systemic circulation. Sepsis, multi-organ failure and death ensue. *, systemic data. #, strong evidence to be harmful only from one paper.

Figure 3.

Summary of the regulation and role of immune mediators in NEC. Green, protective; Grey, inconclusive; and Red, harmful. White text, animal data; purple text, human data; yellow text, animal and human data; black text outline, functional and/or genetic data. Ig, immunoglobulin; IFNγ, interferon gamma; IL, interleukin; IL-1Ra, interleukin-1 receptor antagonist; IL-1R8, IL-1 receptor 8; IL-17R, IL-17 receptor; MyD88, myeloid differentiation factor 88; NF-κB, nuclear factor-κB; NOD-2, nucleotide-binding oligomerisation domain-containing protein 2; PAF, platelet-activating factor; PAF-AH, PAF-acetylhydrolase; RORC, RAR-related orphan receptor C; TNF, tumour necrosis factor; TRIF, toll/IL-1R domain containing adaptor inducing IFNβ; TLR, toll-like receptor; TGF-β, transforming growth factor beta; *, may be protective in NEC, but Ig supplementation has not proven effective; #, strong evidence to be harmful only from one paper.