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Originally published online as doi:10.1189/jlb.0607358 on December 26, 2007

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(Journal of Leukocyte Biology. 2008;83:493-498.)
© 2008 by Society for Leukocyte Biology

The role of epithelial Toll-like receptor signaling in the pathogenesis of intestinal inflammation

Steven C. Gribar, Rahul J. Anand, Chhinder P. Sodhi and David J. Hackam1

Division of Pediatric Surgery, Department of Surgery, Children’s Hospital of Pittsburgh and the University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA

1Correspondence: Division of Pediatric Surgery, Room 4A-486 DeSoto Wing, Children’s Hospital of Pittsburgh, Pittsburgh, PA 15213, USA. E-mail: david.hackam{at}chp.edu

ABSTRACT

Emerging evidence suggests that the innate immune system, comprised of Toll-like receptors (TLRs) and their associated molecules, plays a pivotal role in the regulation of intestinal inflammation and in the response to invading pathogens. Although TLRs are thought to have predominantly beneficial effects in pathogen recognition and bacterial clearance by leukocytes, their dysregulation and unique signaling effects within intestinal epithelia in the setting of inflammation may have devastating consequences. For instance, activation of TLR4 in enterocytes leads to an inhibition of enterocyte migration and proliferation as well as the induction of enterocyte apoptosis—factors that would be expected to promote intestinal injury while inhibiting intestinal repair. TLR signaling has been shown to be abnormal in several intestinal inflammatory diseases, including Crohn’s disease, ulcerative colitis, and necrotizing enterocolitis. This review serves to examine the evidence regarding the patterns of expression and signaling of TLRs in the intestinal mucosa at basal levels and during physiologic stressors to gain insights into the pathogenesis of intestinal inflammation. We conclude that the data reviewed suggest that epithelial TLR signaling—acting in concert with TLR signaling by leukocytes—participates in the development of intestinal inflammation. We further conclude that the evidence reviewed provides a rationale for the development of novel, epithelial-specific, TLR-based agents in the management of diseases of intestinal inflammation.

Key Words: lipopolysaccharide • mucosa • enterocyte • necrotizing enterocolitis • inflammatory bowel disease

THE INTESTINAL MUCOSAL BARRIER DURING INTESTINAL INFLAMMATION: A LEAK IN THE UMBRELLA

The intestinal mucosal barrier has an unenviable job. Burdened with the great responsibility of protecting the host from potentially fatal luminal pathogens and at the same time, providing an absorptive surface for nutrients, the intestinal barrier is part umbrella and part sponge. Central to the great protective nature of the intestinal barrier is its need to sense and respond to proinflammatory bacterial products and to recognize when barrier disruption has occurred. Yet, the magnitude of the response to barrier injury must be regulated appropriately for the injury itself and not more—like an umbrella turned outwards, not only does an exaggerated healing response fail to protect, it can lead to further disruption. Further, from the point of view of the intestine, barrier disruption can have devastating consequences, as manifest by Crohn’s disease, ulcerative colitis, and necrotizing enterocolitis (NEC). An understanding of how the intestinal barrier senses and responds to bacterial products is critical to gaining insights into the pathogenesis of diseases of intestinal inflammation.

Our laboratory and those of others have focused significant attention on understanding the mechanisms by which the intestinal barrier responds to pathogens during conditions of inflammation and what the consequences of such a response may be. To do so, we have focused on the Toll-like receptor (TLR) family of innate immune receptors, a class of molecules made famous by their ability to respond to exogenous and endogenous ligands in macrophages, resulting in activation of the host immune system [1 , 2 ]. Yet, despite a large body of literature describing the expression, regulation, and consequences of TLR regulation in leukocytes in the pathogenesis of sepsis, there is a relative paucity of data that has examined the role of intestinal TLRs in the pathogenesis of intestinal inflammation [3 , 4 ]. We and others have determined that not only do enterocytes express TLRs, but their regulation during periods of stress can have an important impact on their expression, resulting in marked changes in enterocyte function [5 , 6 ]. Despite an established role for TLR signaling in leukocytes in the development of sepsis in general, emerging findings indicate that TLR signaling in enterocytes may play a critical and hitherto underappreciated role in the development of intestinal inflammation. The evidence in support of such a claim will be presented in detail below.

DEFINING THE RECOGNITION PATHWAYS: TLR4 SIGNALING IN THE INTESTINE

To understand the mechanisms that govern TLR4 signaling in enterocytes, we have turned to parallel systems, in which patterns of TLR responsiveness have recently been elucidated. Nusslein-Volhard and colleagues [7 ] first identified Toll protein as a critical protein for normal Drosophila embryo dorsal-ventral polarity using a saturated mutagenesis screen, which was subsequently shown to play a critical role in fungal resistance in the fly [8 ]. The first human homologue of Toll (hToll) was identified in 1997 by Janeway and colleagues [9 ] and was subsequently determined to be a receptor for LPS signaling and was renamed TLR4. Poltorak et al. [10 ] and Hoshino et al. [11 ], who determined that mice expressing a mutant form of hToll (TLR4) were hyporesponsive to endotoxin (LPS), demonstrated a role for TLR4 in mammalian innate immunity. Further, although much of the information in the field of TLR signaling over the past decade has been garnered from experiments performed on leukocytes (see ref. [12 ] or [13 ] for two recent reviews), emerging evidence has provided exciting insights into the role of enterocyte TLR4 signaling in the pathogenesis of intestinal inflammation. Intestinal epithelial cells (IECs), including rat IEC-6 enterocytes [14 , 15 ], primary colonocytes [16 ], HT-29, and T84 colonocytes [17 , 18 ], and mouse rectal CMT93 cells [16 ] have been found to express TLR4, along with the costimulatory molecules myeloid differentiation protein 2 (MD-2) and MyD88. In addition to the expression of TLR4 in enterocytes, several lines of evidence indicate that TLR4 is functionally active within the intestinal mucosa. Specifically, activation by LPS of enterocytes has been shown to lead to changes in proliferation [14 ], NF-{kappa}B activation [17 ], and the release of proinflammatory cytokines [16 , 18 ]. This suggests the possibility that direct signaling by enterocytes in response to TLR ligands could lead to the initiation or propagation of an inflammatory response.

When considering the potential roles of enterocyte signaling in the pathogenesis of intestinal inflammation, one must reconcile the finding that enterocytes are constantly exposed to LPS yet spend most of their time in seemingly peaceful coexistence with the potential pathogens in their midst. This raises the following important question: How does the intestine sense the need to respond to LPS in the environment, and when such a response is deemed to be necessary, how should such signaling be tempered to prevent exuberant stimulation during nondisease states? In addressing these questions, we and others have focused on the regulation of TLR4 during conditions of stress as compared with nonstressed states [5 , 6 , 16 , 19 20 21 22 ]. For instance, Abreu et al. [19 , 20 ] have shown that the extent of the response to LPS in enterocytes may be increased by IFN-{alpha} and -{gamma} in a process that requires an increase in the expression of MD-2 and TLR4. Otte et al. [16 ] have demonstrated that persistent LPS exposure leads to reduced TLR4 expression and increased expression of inhibitory Toll-interacting protein. However, this latter finding lies in opposition to that of Hornef et al. [21 ], who demonstrated that in a small intestinal cell line, continuous exposure to LPS did not alter TLR4 expression. It is possible that changes in TLR4 expression lead to alterations in TLR4 responsiveness. For instance, small intestinal enterocytes, such as IEC-6, express TLR4 in relatively higher amounts and are more sensitive to LPS than colonic Caco-2 cells, which express relatively low levels of TLR4 [20 , 22 ]. We have recently shown that two factors known to be present during intestinal inflammation—namely, hypoxia and high concentrations of endotoxin—lead to increased TLR4 expression in enterocytes in vitro and in vivo [5 ]. These findings raise the possibility that changes in the prevailing inflammatory conditions or the density of luminal bacteria could alter the extent and nature of TLR signaling in enterocytes, leading to the initiation of an inflammatory response within the enterocyte monolayer itself.

THE EFFECTS OF ENTEROCYTE TLR4 SIGNALING ON ENTEROCYTE FUNCTION

In leukocytes, TLR4 signaling is associated with the activation of NF-{kappa}B and the release of proinflammatory cytokines [11 ]. Further, although enterocytes have been identified to be capable of releasing proinflammatory molecules in response to TLR4 activation [14 ], we and others have demonstrated that enterocyte TLR4 signaling leads to effects that are important in the pathogenesis of intestinal inflammation beyond the activation of NF-{kappa}B [23 24 25 ]. For instance, we have demonstrated [23 ] that activation of TLR4 in IEC-6 enterocytes leads to an arrest in the migration of enterocytes into a scraped wound, a process termed intestinal restitution, which is known to play a pivotal role in the ability of the intestine and intestinal mucosa to heal in response to injury. The physiological importance of this observation is found in the fact that intestinal restitution is significantly impaired in experimental NEC [23 , 24 ], a finding recently confirmed by others [25 ]. In understanding the mechanisms mediating the LPS-induced inhibition of enterocyte migration, TLR4 activation was found to cause a RhoA-dependent increase in the formation of stress fibers in enterocytes, leading to an increase in cell-matrix adhesiveness [23 ]. The RhoA-dependent increase in the ability of enterocytes to adhere to the underlying matrix acted to limit cell movement in a manner akin to attempting to drive a car with the parking brakes applied. TLR4 activation in a variety of enterocyte lines was also observed to cause the translocation of β1 integrins from an intracellular pool to the cell surface in a phosphatidylinositol 3-kinase (PI3-K)-dependent manner, which further accounted for the observed inhibition in cell migration that occurred [24 ]. We have also shown that TLR4 activation leads to an increase in enterocyte apoptosis, leading to a loss of barrier integrity [5 ]. Taken together, these findings provide evidence that TLR4 signaling in enterocytes, in addition to activating pathways leading to cytokine release, may directly lead to perturbations in mucosal healing and further exacerbate the inflammatory response within the intestinal mucosa.

A ROLE FOR ENTEROCYTE TLR4 SIGNALING IN THE PATHOGENESIS OF NEC

To understand the potential role of enterocyte TLR4 in the pathogenesis of intestinal inflammation, we have turned to an important clinical disease characterized by the presence of intestinal inflammation and systemic sepsis, namely, NEC, which is the leading cause of death from gastrointestinal disease in preterm infants [26 ], for which reliable animal models exist, and is currently one of the leading causes of death of newborns in the United States overall, with a mortality rate of nearly 15% [27 ]. We have recently established a critical role for enterocyte TLR4 activation in the pathogenesis of NEC [5 ]. Specifically, we found that NEC in mice and humans is associated with increased expression of TLR4 in the intestinal mucosa and as mentioned previously, that physiological stressors associated with NEC development—namely, exposure to LPS and hypoxia—sensitize the murine intestinal epithelium to LPS through up-regulation of TLR4 [5 ]. In support of a critical role for TLR4 in the development of NEC, TLR4 mutant C3H/HeJ mice were protected from the development of NEC compared with wild-type C3H/HeOUJ littermates [5 ], a finding consistent with previous work by Caplan and colleagues [6 ]. TLR4 activation in vitro led to increased enterocyte injury by apoptosis and reduced healing as a result of an inhibition of enterocyte migration and proliferation. This latter finding suggests a role for enterocyte TLR4 in the regulation of intestinal mucosal repair. In support of this possibility, increased NEC severity in wild-type C3H/HeOUJ mice resulted from increased enterocyte apoptosis and reduced enterocyte restitution and proliferation compared with TLR4 mutant mice. TLR4 signaling also led to increased serine-phosphorylation of intestinal focal adhesion kinase (FAK), a molecule necessary for efficient enterocyte migration. Remarkably, TLR4 coimmunoprecipitated with FAK in enterocytes, and small interfering RNA-mediated FAK inhibition restored enterocyte migration after TLR4 activation, demonstrating that the FAK-TLR4 association regulates intestinal healing. Taken together, these findings demonstrate a critical role for TLR4 signaling in the intestinal epithelium in the development of NEC through effects on enterocyte injury and repair [5 ].

It is noteworthy that although abundant evidence indicates that enterocytes have the capacity to respond to TLR4, these studies do not exclude the possibility that TLR4 signaling in leukocytes may contribute to the manifestations of intestinal inflammation. In support of a role for resident epithelial cells in the pathogenesis of epithelial inflammation, several authors have performed studies in bone marrow chimeric mice, in which the leukocytes or epithelia bear mutations in TLR signaling components. Specifically, Noulin et al. [28 ] have used MyD88 chimeras to demonstrate that the pulmonary epithelium plays a key role in the development of pulmonary inflammation in response to inhaled endotoxin, a finding supported by Hajjar et al. [29 ] in a model of bacterial pneumonia. Similarly, Schilling et al. [30 ] demonstrated in a TLR4 chimeric system that the uroethelium along with invading leukocytes act together in the development of inflammation in response to uropathogenic Escherichia coli. It is important to note that in the absence of experimental evidence that undertakes this approach in the intestine, the relative role of the enterocyte versus the leukocyte in the development of intestinal inflammation remains incompletely addressed.

BEYOND TLR4: A ROLE FOR "OTHER" TLRs IN THE PATHOGENESIS OF INTESTINAL INFLAMMATION

In addition to TLR4, other TLRs have been shown to be expressed within the intestinal epithelium (see Table 1 ), suggesting that they may play a role in the pathogenesis of intestinal inflammation. For instance, TLR2–/– and TLR9–/– mice were recently found to develop more severe colonic inflammation compared with their respective wild-type littermates [44 , 45 ]. These findings suggest that TLR2 and TLR9 play a role in the maintenance of intestinal homeostasis and/or that these molecules may play a role in modulating the extent of intestinal inflammation that develops [45 ]. In support of this latter concept, treatment of mice with the TLR9 ligand CpG-DNA ameliorated the severity in dextran sodium sulfate (DSS) colitis, hapten-induced colitis, and spontaneous colitis in IL-10 knockout mice [46 ]. This finding may lie in contrast to other reports that have shown TLR9-deficient mice to develop less severe chronic colitis as compared with wild-type littermates [47 ] and that inhibition of TLR9 using adenoviral oligodeoxynucleotides reduced the severity of experimental colitis in a DSS-colitis model [47 ]. A protective role for TLR3 signaling in the pathogenesis of intestinal inflammation has also been suggested, as administration of the TLR3 ligand polyinosinic-polycytidylic acid prior to the induction of DSS colitis protected against the severity of the disease that developed, and this effect was not observed in TLR3–/– mice [48 ]. Although these findings clearly implicate TLR signaling in the development of intestinal inflammation, it should be acknowledged that this may occur in response to signaling in enterocytes themselves or may develop secondary to the activation of proinflammatory cascades in leukocytes. As well, the activity of various TLRs within the epithelium may be modified by exogenous agents in a positive-feedback loop. For instance, viral infection could activate epithelial TLR3, -7, or -8, which could then heighten the presentation of antigen and in turn, generate a primary immune response and/or recruit memory cells that recognize viral peptides and thus, control viral replication. Accordingly, additional study is required to more adequately determine the relative contribution of epithelial TLR signaling compared with TLR signaling in myeloid cells and its potential modification by other immune components in the pathogenesis of intestinal inflammation.


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  		Table 1. The Expression of TLRs in Enterocytes and Colonocytes

INSIGHTS INTO THE ROLE OF INTESTINAL ENTEROCYTE SIGNALING GAINED FROM HUMAN GENETIC STUDIES

In addition to the data obtained from the in vitro and in vivo studies described above, evidence for the role of TLR4 signaling in the pathogenesis of intestinal inflammation and systemic sepsis may be found by examining the results of genetic analyses of patients with inflammatory bowel disease (IBD) and sepsis. For instance, the Asp299Gly mutation in TLR4 is associated with an increased risk of IBD [49 , 50 ]. In patients with ulcerative colitis, the presence of pancolitis, the most severe manifestation of the disease, is significantly more common in patients with the TLR1 Arg80Thr polymorphism and the TLR2 Arg753Gly polymorphism compared with patients that do not have these mutations, and patients with ulcerative colitis with the Ser249Pro polymorphism had a lower incidence of proctitis [51 ]. Of note, in patients with Crohn’s disease, patients with the TLR1 Ser602Ile polymorphism were less likely to develop ileal disease as compared with patients without this mutation [51 ]. To date, TLR polymorphisms have not been associated with NEC [52 ], although further study is necessary, and although these reports do not reliably discern whether the disease manifestations are reflective of TLR signaling on enterocytes versus on leukocytes that migrate into the intestinal mucosa, they do provide strong evidence for the role of TLRs in the pathogenesis of intestinal inflammation.

PUTTING IT ALL TOGETHER: THE ROLE OF INTESTINAL TLR SIGNALING IN THE PATHOGENESIS OF INTESTINAL INFLAMMATION

Based on the evidence reviewed above, we propose the following model to explain the role of enterocyte TLR signaling in the pathogenesis of intestinal inflammation. During nondiseased states, epithelia peacefully coexist with the bacteria around them, without the initiation of a proinflammatory response (Fig. 1A ). However, after an episode of stress, such as a hypoxic insult or remote infection, leading to the release of proinflammatory cytokines such as IFN-{alpha}, TLR4 responsiveness within the enterocyte changes (Fig. 1B) . This results in an increase in enterocyte death by apoptosis and a corresponding loss of healing capacity, as manifest by reduced proliferation and migration. Taken together, these factors promote bacterial translocation, resulting in activation of the subepithelial immune system and the development of intestinal inflammation and systemic sepsis.


Figure 1
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  		Figure 1. Model describing the role of enterocyte TLR signaling in the pathogenesis of intestinal inflammation. (A) Basal conditions, in which enterocyte TLR signaling may contribute to intestinal homeostasis. (B) After exposure to physiological stressors, such as remote infection, hypoxia, or exposure to high concentrations of LPS, TLR signaling within the enterocyte may result in profound and deleterious effects on the epithelial monolayer, including the release of proinflammatory cytokines, the induction of epithelial damage through apoptosis, and the inhibition of intestinal repair. These effects may be initiated or propagated by the activities of TLR-activated leukocytes. As a result, barrier failure occurs, leading to the development of bacterial translocation and intestinal inflammation.

Although the model depicted in Figure 1 provides a useful framework to allow the study of the role of enterocyte TLR signaling in the pathogenesis of intestinal inflammation, we admit that it leaves many important questions unanswered. For instance, what is the role of enterocyte TLR signaling during basal states, and what are the factors that transition TLR signaling from a seemingly protective state at rest to a clearly deleterious state during conditions of inflammation? Further, what is the relative contribution of TLR signaling at enterocytes versus leukocytes, and does TLR signaling result in similar responses from both cell types? Finally, what is the full spectrum of TLR mutations in humans, and how do these lead to the development of intestinal inflammation? Much attention is likely to be placed in answering these questions, and it is our firm belief that the answers derived will provide novel, therapeutic insights into the management of diseases of intestinal inflammation and most importantly, to provide comfort for the patients who suffer with them.

ACKNOWLEDGEMENTS

D. J. H. is supported by R01GM078238-01 from the National Institutes of Health (NIH) and the State of Pennsylvania Tobacco Settlement Fund. S. C. G. is supported in part by the Loan Repayment Program for Pediatric Research of the NIH and a Resident Research Award from the American College of Surgeons.

Received June 8, 2007; revised October 16, 2007; accepted November 28, 2007.

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