Enterocyte TLR4 Mediates Phagocytosis and Translocation of Bacteria Across the Intestinal Barrier

Neal, Matthew D.; Leaphart, Cynthia L.; Levy, Ryan M.; Prince, José M.; Billiar, Timothy R.; Watkins, Simon C.; Li, Jun; Çetin, Selma; Ford, Henri R.; Schreiber, Alan D.; Hackam, David J.

doi:10.4049/jimmunol.176.5.3070

Cited by 353 publications

(278 citation statements)

References 57 publications

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“…Given the current observation that mice in which TLR4 had been deleted from the intestinal epithelium (TLR4 Δvillin ) also had normal intestinal perfusion when subjected to experimental NEC, these findings raise the intriguing possibility that TLR4 signals first within the intestinal epithelium-where bacteria rich in TLR4 ligands are first encountered-which is then followed by activation within the endothelium leading to NEC. In support of this paradigm, we have demonstrated that TLR4 activation within the epithelium promotes bacterial translocation in two ways: by disrupting the intestinal barrier through increased enterocyte apoptosis and reduced mucosal repair (5,11) and through direct transcellular passage in which TLR4 mediates the uptake of TLR4 ligands by enterocytes (18). The subsequent activation of TLR4 within the endothelium then results in the impaired perfusion of the subjacent intestinal microcirculation through a reduction in eNOS, which leads to intestinal necrosis and the development of NEC.…”

Section: Discussionmentioning

confidence: 87%

Endothelial TLR4 activation impairs intestinal microcirculatory perfusion in necrotizing enterocolitis via eNOS–NO–nitrite signaling

Yazji

Sodhi²,

Lee³

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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202

171

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Necrotizing enterocolitis (NEC) is a devastating disease of premature infants characterized by severe intestinal necrosis and for which breast milk represents the most effective protective strategy. Previous studies have revealed a critical role for the lipopolysaccharide receptor toll-like receptor 4 (TLR4) in NEC development through its induction of mucosal injury, yet the reasons for which intestinal ischemia in NEC occurs in the first place remain unknown. We hypothesize that TLR4 signaling within the endothelium plays an essential role in NEC development by regulating perfusion to the small intestine via the vasodilatory molecule endothelial nitric oxide synthase (eNOS). Using a unique mouse system in which we selectively deleted TLR4 from the endothelium, we now show that endothelial TLR4 activation is required for NEC development and that endothelial TLR4 activation impairs intestinal perfusion without effects on other organs and reduces eNOS expression via activation of myeloid differentiation primary response gene 88. NEC severity was significantly increased in eNOS −/− mice and decreased upon administration of the phosphodiesterase inhibitor sildenafil, which augments eNOS function. Strikingly, compared with formula, human and mouse breast milk were enriched in sodium nitrate-a precursor for enteral generation of nitrite and nitric oxide-and repletion of formula with sodium nitrate/nitrite restored intestinal perfusion, reversed the deleterious effects of endothelial TLR4 signaling, and reduced NEC severity. These data identify that endothelial TLR4 critically regulates intestinal perfusion leading to NEC and reveal that the protective properties of breast milk involve enhanced intestinal microcirculatory integrity via augmentation of nitrate-nitrite-NO signaling.neonatal inflammation | prematurity | infant formula | neonatal nutrition | sepsis N ecrotizing enterocolitis (NEC) is the leading cause of death from gastrointestinal disease in the premature infant and is gradually increasing in frequency (1). The defining pathological feature of NEC is the presence of patchy areas of ischemia and necrosis of the small and large intestine (2). Although prematurity is the leading risk factor for NEC development, breast milk administration has been identified as the most important protective strategy (3). Importantly, the mechanisms that lead to the acute development of intestinal necrosis in the premature intestine and factors within breast milk that may prevent NEC remain largely unexplored.In seeking to understand the underlying biological mechanisms that lead to NEC, we and others have identified a critical role for the innate immune receptor toll-like receptor 4 (TLR4) in NEC pathogenesis, because mice deficient in TLR4 showed reduced mucosal inflammation and reduced intestinal necrosis in experimental NEC (4, 5). Microcirculatory perfusion of the premature intestine is primarily regulated by the vasodilator nitric oxide (NO), which is generated through the activity of endothelial NO synthase (eNOS) (6). ...

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Section: Discussionmentioning

confidence: 87%

Endothelial TLR4 activation impairs intestinal microcirculatory perfusion in necrotizing enterocolitis via eNOS–NO–nitrite signaling

Yazji

Sodhi²,

Lee³

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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202

171

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“…To do so, we treated the intestinal crypt-like cell line IEC-6, which we have previously shown to express TLR4 (5,11,23) with LPS and determined the subsequent effects on ER stress and apoptosis. As shown in Fig.…”

Section: Tlr4 Activation Induces Er Stress and Apoptosis In Iec-6 Entmentioning

confidence: 99%

Toll-like Receptor 4-mediated Endoplasmic Reticulum Stress in Intestinal Crypts Induces Necrotizing Enterocolitis

Afrazi

Branca

Sodhi

et al. 2014

Journal of Biological Chemistry

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159

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“…In this regard, several investigators have established that DAMPs and PAMPs are recognized by TLRs in many cells, including epithelial cells: a list of the TLRs and their cognate ligands appears in Table 1. Although current dogma suggests that circulating leukocytes play a central role in the coordination of the immune response, emerging evidence suggests that the epithelium also plays a key role in the recognition and response to various "danger molecules" (27)(28)(29)(30)(31). This review will examine in detail the various roles of epithelial signaling via TLRs in the development of common, and often devastating, mucosal inflammatory conditions.…”

Section: Defining the Controversies In The Pathogenesis Of Mucosal Inmentioning

confidence: 99%

No Longer an Innocent Bystander: Epithelial Toll-Like Receptor Signaling in the Development of Mucosal Inflammation

Gribar

Richardson

Sodhi

et al. 2008

Mol Med

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109

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Diseases of mucosal inflammation represent important causes of morbidity and mortality, and have led to intense research efforts to understand the factors that lead to their development. It is well accepted that a breakdown of the normally impermeant epithelial barrier of the intestine, the lung, and the kidney is associated with the development of inflammatory disease in these organs, yet significant controversy exists as to how this breakdown actually occurs, and how such a breakdown may lead to inflammation. In this regard, much work has focused upon the role of the epithelium as an "innocent bystander," a target of a leukocyte-mediated inflammatory cascade that leads to its destruction in the mucosal inflammatory process. However, recent evidence from a variety of laboratories indicates that the epithelium is not merely a passive component in the steps that lead to mucosal inflammation, but is a central participant in the process. In addressing this controversy, we and others have determined that epithelial cells express Toll-like receptors (TLRs) of the innate immune system, and that activation of TLRs by endogenous and exogenous ligands may play a central role in determining the balance between a state of "mucosal homeostasis," as is required for optimal organ function, and "mucosal injury," leading to mucosal inflammation and barrier breakdown. In particular, activation of TLRs within intestinal epithelial cells leads to the development of cellular injury and impairment in mucosal repair in the pathogenesis of intestinal inflammation, while activation of TLRs in the lung and kidney may participate in the development of pneumonitis and nephritis respectively. Recent work in support of these concepts is extensively reviewed, while essential areas of further study that are required to determine the significance of epithelial TLR signaling during states of health and disease are outlined.

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Enterocyte TLR4 Mediates Phagocytosis and Translocation of Bacteria Across the Intestinal Barrier

Cited by 353 publications

References 57 publications

Endothelial TLR4 activation impairs intestinal microcirculatory perfusion in necrotizing enterocolitis via eNOS–NO–nitrite signaling

Endothelial TLR4 activation impairs intestinal microcirculatory perfusion in necrotizing enterocolitis via eNOS–NO–nitrite signaling

Toll-like Receptor 4-mediated Endoplasmic Reticulum Stress in Intestinal Crypts Induces Necrotizing Enterocolitis

No Longer an Innocent Bystander: Epithelial Toll-Like Receptor Signaling in the Development of Mucosal Inflammation

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