Chromatin as alarmins in necrotizing enterocolitis

Abstract

Necrotizing enterocolitis (NEC) is a severe gastrointestinal disease primarily affecting premature neonates, marked by poorly understood pro-inflammatory signaling cascades. Recent advancements have shed light on a subset of endogenous molecular patterns, termed chromatin-associated molecular patterns (CAMPs), which belong to the broader category of damage-associated molecular patterns (DAMPs). CAMPs play a crucial role in recognizing pattern recognition receptors and orchestrating inflammatory responses. This review focuses into the realm of CAMPs, highlighting key players such as extracellular cold-inducible RNA-binding protein (eCIRP), high mobility group box 1 (HMGB1), cell-free DNA, neutrophil extracellular traps (NETs), histones, and extracellular RNA. These intrinsic molecules, often perceived as foreign, have the potential to trigger immune signaling pathways, thus contributing to NEC pathogenesis. In this review, we unravel the current understanding of the involvement of CAMPs in both preclinical and clinical NEC scenarios. We also focus on elucidating the downstream signaling pathways activated by these molecular patterns, providing insights into the mechanisms that drive inflammation in NEC. Moreover, we scrutinize the landscape of targeted therapeutic approaches, aiming to mitigate the impact of tissue damage in NEC. This in-depth exploration offers a comprehensive overview of the role of CAMPs in NEC, bridging the gap between preclinical and clinical insights.

Keywords: CAMPs; HMGB1; PRRs; TLR4; cell-free DNA; eCIRP; inflammation; necrotizing enterocolitis.

Figure 1

CAMPs, PRRs, and the Development of NEC. CAMPs, including eCIRP, cfDNA, exRNA, HMGB1, histones, and NETs are released upon cellular stress. CAMPs are recognized and activate downstream PRR pathways including TLRs (especially TLR4 and TLR9), cGAS-STING, RAGE, RIG-1, AIM2, and NLRP3. Activation of immune sensors leads to release of pro-inflammatory mediators and causes intestinal inflammation, enterocyte injury and cell death, intestinal barrier dysfunction, bacterial translocation, and impaired microcirculation, all contributing to NEC development. CAMP, chromatin-associated molecular patter; PRR, pattern recognition receptor; NEC, necrotizing enterocolitis; eCIRP, extracellular cold-inducible RNA binding protein; cfDNA, cell-free DNA; exRNA, extracellular RNA; mtDNA, mitochondrial DNA; HMGB1, high mobility group box 1; NETs, neutrophil extacellular traps; TLR, toll-like receptor; TREM-1, triggering receptor expressed on myeloid cells-1; RAGE, receptor for advanced glycation end-products; cGAS, cyclic GMP-AMP (cGAS), STING, stimulator of interferon genes; RIG-1, retinoic acid-inducible gene-I; AIM2, absent in melanoma-2; NLRP3, nod-like receptor family pyrin domain containing-3.