Heme oxygenase-1 confers protection and alters T-cell populations in a mouse model of neonatal intestinal inflammation

Abstract

Background: Necrotizing enterocolitis (NEC), an intestinal inflammatory disease affecting premature infants, is associated with low regulatory T (Treg) to effector T (Teff ) cell ratios. We recently demonstrated that heme oxygenase-1 (HO-1) deficiency leads to increased NEC development. Here, we investigated the effects of HO-1 on T-cell proportions in a murine NEC-like injury model. Methods: Intestinal injury was induced in 7-d-old wildtype (WT) or HO-1 heterozygous (HO-1 Het) pups by formulafeeding every 4 h for 24-78 h by oral gavage and exposures to 5%O 2 . Controls remained breastfed. HO-1 was induced in WT pups by administering heme preinjury induction. Lamina propria T cells were identified by flow cytometry. For adoptive transfer studies, WT splenic/thymic Tregs were injected intraperitoneally into HO-1 Het pups 12-24 h preinduction. results: Het mice showed increased intestinal injury and decreased Treg/Teff ratios. Genes for pattern recognition (Toll-like receptor-4, C-reactive protein, MyD88) and neutrophil recruitment increased in Het pups after NEC induction. Inducing intestinal HO-1 decreased NEC scores and incidence, and increased Treg/Teff ratios. Moreover, adoptive transfer of Tregs from WT to HO-1 Het pups decreased NEC scores and incidence and restored Treg/Teff ratios. conclusion: HO-1 can change Treg proportions in the lamina propria of young mice under inflammatory conditions, which might, in part, confer intestinal protection.n EC is a devastating disease of premature infants.Characterized by intestinal inflammation, it can progress rapidly to intestinal necrosis. Its incidence correlates inversely with low birth weight and gestational age, reaching ~7% in infants weighing 500-1,500 g. Unfortunately, 20-40% of NEC patients need to undergo surgery, which increases mortality up to 50% and places these infants at higher risk for developing long-term sequelae, such as short bowel syndrome and neurodevelopmental impairments (1).Although advances in the understanding of its pathophysiology have been made in the last decades, the pathogenesis of NEC remains incompletely understood. Thus, current prevention and treatment strategies are limited. Three factors are generally present when NEC occurs: (i) an immature intestinal barrier and immune system; (ii) enteral feedings; and (iii) a putative bacterial component. A genetic predisposition, an in utero maternal or fetal insult (hypoxia), and/or a highly immune-reactive intestinal mucosa may then cause the initial inflammation that precedes NEC (2).Several studies have demonstrated the importance of the innate immune system in the pathophysiology of NEC. For example, a significant component is the pattern recognition of pathogens through Toll-like receptor (TLR)-4 (3,4). Also, a reduction in Paneth and in mucin-producing goblet cells (5,6) and an increase in proinflammatory mediators (i.e., TNF-α, IL-1, -6, -8, and platelet-activating factor) are associated with NEC (7).However, less attention has been given to the adaptive immune system. The fact th...

Modulation of antigen processing by haem‐oxygenase 1. Implications on inflammation and tolerance

“…Similar observations were made in mouse models for inflammatory diseases, such as in lactobacillus‐mediated infection where HO‐1 activity was required to efficiently produce mesenteric Foxp3 + CD25 + CD4 + T cells . Moreover, transfer of wild‐type regulatory T cells into HO‐1 heterozygous mice restored the ratios between regulatory and effector T cells and reduced inflammation in a model of necrotizing enterocolitis, supporting a possible direct role for HO‐1 in the generation and function of regulatory T cells . Hence, the HO‐1–CO system arises as a powerful candidate to restrict antigen presentation to T cells in vivo and also to impair the activation of lymphocytes in transplantation and autoimmunity.…”

“…125 Moreover, transfer of wild-type regulatory T cells into HO-1 heterozygous mice restored the ratios between regulatory and effector T cells and reduced inflammation in a model of necrotizing enterocolitis, supporting a possible direct role for HO-1 in the generation and function of regulatory T cells. 126 Hence, the HO-1-CO system arises as a powerful candidate to restrict antigen presentation to T cells in vivo and also to impair the activation of lymphocytes in transplantation and autoimmunity. Furthermore, the generation of regulatory T cells during bacteria-dependent inflammation and graft acceptance seems to depend on the HO-1 activity.…”

Heme Oxygenase Activity and Heme Binding in a Neonatal Mouse Model

“…Although the pathogenesis of cholestasis associated with severe hemolysis was not our focus, our findings support the notion that there are several existing physiologic systems (HO, heme/hemoglobin-binding proteins, hemopexin [19], albumin, and haptoglobin [5]) available to attend to the potential toxicity of FH. Deficiencies among any of those systems should be evaluated when considering the role of HO deficiency in the pathogenesis of various oxidative injuries in the neonate [17,20,21]. Our data affirm differences between newborn and adult mice with respect to HO activity at baseline and after exposure to FH or MHA.…”

“…One- and 5-week-old wild-type (Wt) FVB and HO-1 heterozygous (Het, HO-1 +/- ) mice were used [16,17]. One-week-old mice were kept with their mothers until sacrificed.…”

In VivoHemin Conditioning Targets the Vascular and Immunologic Compartments and Restrains Prostate Tumor Development

“…Remarkably, heme directly regulates various molecular and cellular processes, has been shown to act as a Tcell mitogen in vitro (39) and exerts mild proinflammatory responses encompassing the activation of macrophages and polymorphonuclear cells (40)(41)(42). Furthermore, recent findings have shown that oral administration of heme prior to induction of necrotizing enterocolitis decreased disease incidence and increased Treg/Teff ratios (43). In addition, Konrad and collaborators (44) demonstrated that topical administration of hemin was protective against pulmonary inflammation.…”