Paneth cells and innate mucosal immunity : Current Opinion in Gastroenterology (original) (raw)
Introduction
Paneth cells and their diverse, secreted effectors are implicated in mucosal health and disease. The epithelial monolayer of the gastrointestinal tract provides a physical barrier between the external environment and the circulation. Nutrient absorption occurs at apical brush borders that are exposed to a lumen colonized by a resident microflora and to a dietary influx of microorganisms. In this setting, epithelial transport must be balanced by keeping most microbial cell populations in check, and the low bacterial numbers in small intestine relative to the distal ileum, cecum, and colon suggest that innate immune mechanisms exist to counter microbial colonization. The secretion of gene-encoded antimicrobial peptides and additional host defense proteins by small intestinal Paneth cells plays a major role in mediating this activity [1,2]. Paneth cells populate the base of the crypts of Lieberkühn in the small intestine of most mammals [3,4], and their unique morphology is characterized by an extensive endoplasmic reticulum and Golgi network that direct large dense core secretory granules to the apical membrane (Fig. 1). For a historical perspective on early studies of this cell, please see [5], which includes original depictions of these cells by Schwalbe in 1867 and Paneth's refinements and insights in 1888.
The Paneth cell
Paneth cells and the enteric epithelial barrier
Paneth cell secretory granules are rich in diverse host defense proteins and peptides, including α-defensins, secretory phospholipase A2 (sPLA2, Pla2g2a), lysozyme, lipopolysaccharide (LPS)-binding protein, RegIII-γ, and xanthine oxidase, matrix metalloproteinase 7 (MMP7), CD95 ligand, IgA, CD1d, cysteine-rich intestinal polypeptide (CRIP), CD15, and metallothionein, and an array of proinflammatory mediators that includes interleukin-17A (IL-17A), tumor necrosis factor-α (TNF-α), IL-1β, and lipokines (Fig. 2) [3,4,6,7]. All occur at highest concentration in fully differentiated Paneth cells that occupy the base of small intestinal crypts [3]. Disruptions to Paneth cell homeostasis may lead to induced autophagy, endoplasmic reticulum stress, unfolded protein responses, and apoptosis, leading to ileitis and enhanced sensitivity to colitis [6–8,9•]. Such studies provide evidence for the varied roles by which this cell contributes to innate immune responses and the maintenance of homeostasis in the lower gastrointestinal tract [4].
Secretory products of the Paneth cell
Mechanisms that regulate Paneth cell maturation provide insights into their role in innate immunity and in intestinal homeostasis. Four major epithelial cell lineages, absorptive enterocytes, goblet cells, enteroendocrine cells, and Paneth cells populate the adult small intestine, and they are renewed continually from mitotically active, transit-amplifying cell progenitors that reside in crypts of Lieberkühn [10–13]. Absorptive enterocytes live 3–5 days as they ascend from crypts to villus tips, apoptose, and are exfoliated, but Paneth cell lifetimes are much longer, estimated at 70 days or more by label retention experiments in mice. Paneth cell progenitors accumulate lineage-specific markers as they descend to the crypt base toward increasing levels of Wnt ligand [14,15]. Certain Paneth cell-specific genes are Wnt targets and serve as markers of the lineage, including α-defensins, and β-catenin and T-cell factor-4 (TCF-4) mediate transcription of these genes [14,16].
Advances in understanding regulatory mechanisms in Paneth cell biology have been compromised by a lack of Paneth cell lines, but recent studies show promise using organoid culture conditions [17••,18••]. In one study, long-term cultures of single crypts with Lgr5+ cells or using single Lgr5+ cells alone established organoids that underwent crypt fission, had villus-like epithelial structures, and contained the four major epithelial lineages expressing appropriate differentiation markers [18••] (Fig. 3a, b). Independently, long-term cultures of neonatal small and large intestinal explants with underlying stromal elements grew at an air–liquid interface as organoids with multilineage differentiation in Wnt responsive fashion [17••] (Fig. 3c, d). Lgr5+ and Bmi1+ putative intestinal stem cells expanded when treated with Wnt agonists. The availability of these reductionist, self-organizing, crypt–villus systems should enable Paneth cell responses and microbial crosstalk to be investigated in molecular detail (Fig. 3).
Establishment of intestinal crypt culture system
Paneth cell responses to microbial exposure
The presence of lysozyme and α-defensins in Paneth cell granules suggested a mucosal immune role years ago [19–22], and recent studies implicate the lineage directly in enteric host defense. Paneth cell ontogeny is independent of luminal bacteria, bacterial antigens, or dietary constituents, as shown by normal Paneth cell development in germ-free mice, in sterile organoids [17••,18••], and under aseptic conditions [23,24]. Also, human Paneth cells appear in the first trimester of gestation and express α-defensin genes in utero, further evidence that they differentiate independently of infectious stimuli [25–27].
Paneth cell α-defensins both contribute enteric innate immunity and determine the composition of the small intestinal microbiome [28,29••]. Mice lacking the mouse Paneth cell pro-α-defensin convertase MMP7 were deficient in clearing orally administered, noninvasive _Escherichia coli_[30]. In mouse models of cystic fibrosis, undissolved Paneth cell secretory granules accumulate in mucus-occluded crypts, leading to small intestinal bacterial overgrowth by Enterobacteriaceae [31,32]. Possibly, reduced availability of luminal α-defensins could modify the resident microbiota toward a more proinflammatory population and, thus, contribute to disease. Also, transgenic mice expressing human HD5 in Paneth cells [_DEFA5_-transgenic (+/+ mice)] are immune to oral challenge with wild-type Salmonella enterica serovar Typhimurium as a result of adding a single new α-defensin to Paneth cell secretions [28]. Whether that immunity is mediated by direct peptide-mediated bactericidal activity or by modifying the composition of the resident microflora has been unclear, but recent evidence strongly favors the latter interpretation.
α-Defensins secreted by Paneth cells determine the composition of the mouse small intestinal microbiome, apparently by selecting for peptide-tolerant microbial species as residents in that microbial ecosystem [29••]. Analysis of bacterial phyla and groups in the distal 15 cm of mouse small bowel in individual _DEFA5_-transgenic (+/+), MMP7 −/−, and appropriate littermate controls showed marked changes in the microflora. For example, Firmicutes represented 63.4% of bacteria in the MMP7 −/− small intestine, but only 25.5% in the DEFA5 (+/+)-transgenic mice. In contrast, the percentage of Bacteroidetes was only 17.5% in the MMP7 −/− mouse, but 69.3% in the DEFA5 (+/+)-transgenic mouse distal small bowel. Thus, the small bowel microflora of defensin deficient vs. defensin complemented mice was genotype-dependent and showed reciprocal differences. Because a resident microflora is essential in inflammatory bowel disease (IBD) pathogenesis [33], the quantity and/or the repertoire of Paneth cell α-defensins and other gene products may influence gastrointestinal inflammation by shaping a healthy microbiome or one that promotes disease in genetically predisposed individuals.
In addition to Paneth cell secretory proteins whose expression is programmed during lineage determination, newly induced Paneth cell gene products also influence or respond to the microflora during postnatal crypt ontogeny in mice. Levels of Paneth cell markers, including α-defensins, Pla2g2a, MMP7, and lysozyme, are similar in germ-free and conventionally reared mice, and the transcriptional profiles of the germ-free and colonized small intestine are also generally similar [34–37]. Nevertheless, certain mouse Paneth cell granule constituents are inducible in response to microbial colonization or to changes in the microflora, as exemplified by the increased abundance of bactericidal ribonuclease angiogenin-4 and the C-type lectin RegIIIγ in mice monocolonized with Bacteroides thetaiotaomicron as compared with germ-free controls [35,38]. Additionally, in mice lacking the Toll-like receptor adapter MyD88, small intestinal expression of RegIIIγ, RegIIIβ, CRP-ductin, and RELMβ is induced by oral bacterial infection with _Listeria monocytogenes_[39]. In this model, cell-autonomous Paneth cell MyD88 activation, not activation in cells of myeloid origin, mediates signaling to maintain intestinal homeostasis to the infectious challenge [39,40]. Also, in an oral challenge C57BL/6 mouse model of infection, Toxoplasma gondii induced Tlr9 mRNA accumulation, an increase in type I interferon (IFN) mRNA levels, and elevated Crp3 and Crp5 mRNA expression, and in Tlr9 −/− mice the responses could be replicated with IFN-β administration and were abrogated in type I interferon receptor (IFNAR) −/− mice. The T. gondii effects are mediated by Tlr9-dependent production of type I IFNs, but whether the induction of Crps 3 and 5 is a direct Paneth cell response to IFN or a paracrine response to a different mediator remains unknown. Interpretation of α-defensin induction is complicated in mice, because the C57BL/6 mouse defensin locus differs from other reference strains (M.T. Shanahan et al., submitted) and contains several copies of the Crp3 and Crp5 genes [41]. Therefore, whether induction results from enhanced transcription and posttranscriptional processing of already active genes or transcriptional activation of Crp genes that were silent prior to the infectious process cannot be distinguished at this time.
Paneth cell secretory responses
Paneth cells release secretory granules in a dose-dependent manner following interaction with bacterial antigens and in response to pharmacologic stimulation [42–45]. α-Defensin secretion by Paneth cells constitutes a major source of bactericidal peptide activity released into the lumen of isolated mouse small intestinal crypts [45], and Paneth cells of isolated human crypts also secrete α-defensin-rich granules when exposed to bacteria or their antigens [46,47]. Although the sensors remain unknown, Paneth cell secretion induced by carbamylcholine and bacterial antigens is regulated by cytosolic [Ca2+] mobilized from both intracellular stores and influx of extracellular Ca2+[42,48]. Inhibiting influx of Ca2+ by selective blockers of the Ca2+-activated intermediate conductance K+ channel KCa3.1 (also known as Kcnn4 and mIKCa1) attenuates Paneth cell secretion by approximately 50% as a result of failing to sustain the Ca2+ signal [48].
The calcium-activated KCa3.1 channel recently has been implicated in IBD. KCa3.1 has two major sites of expression: T lymphocytes and Paneth cells, and, in both settings, it enables Ca2+ influx for T-cell activation and to sustain Paneth cell secretion. T cells from KCa3.1 −/− mice have reduced Ca2+ influx and IL-2 production following T-cell receptor ligation. KCa3.1 −/− mice and mice treated with selective KCa3.1 blockers developed less severe colitis in two experimental models of IBD (Fig. 4 and [49•]), and the attenuated disease phenotype was T-cell-dependent [49•]. Also, a genome-wide association study (GWAS) has identified KCNN4 (KCa3.1) as a potential susceptibility factor in ileal Crohn's disease in the Australian and New Zealand populations investigated [50•], and the association between a certain KCNN4 SNP and Crohn's ileitis is consistent with the phenotype of KCa3.1-deficient mice [49•]. Interestingly, patients with NOD2 mutations [51] were reported to have lower KCNN4 expression in noninflamed ileum [50•], though biochemical confirmation of that association remains to be completed. Whether defects in KCa3.1 impair Paneth cell secretion sufficiently to diminish levels of luminal α-defensins (and other secreted components, see Fig. 2) in vivo is not known, but such a decrease resulting from impaired Paneth cell secretion could skew the small intestinal microbiome toward a more proinflammatory population. In the mouse models, however, the dampening of T-cell activation due to KCa3.1 deficiency or blockade overcomes the hypothetical proinflammatory contribution of a Paneth cell defect, thus attenuating experimental colitis.
Decreased severity of colitis induced by KCa3.1−/− CD4+CD25−CD45RBhi donor T cells
Paneth cell homeostasis and disease
Defects in Paneth cell physiology may predispose individuals to infectious challenges and to IBD. The Paneth cell lineage is committed to the biosynthesis of secretory proteins as components of dense core granules (Figs 1 and 2). Defects that target secretory pathways or induce autophagy or endoplasmic reticulum stress selectively in intestinal epithelium appear to have disproportionately adverse effects on endoplasmic reticulum-rich Paneth cell homeostasis and contribute to IBD pathogenesis. For example, Atg16l1 is a Crohn's disease susceptibility gene whose product participates in maintaining the subcellular distribution of the cell autophagy machinery. Paneth cells of mice that are hypomorphic for Atg16l1 are defective in secretion, activate expression of proinflammatory mediators (see above), and are highly autophagous, mimicking the morphology of Paneth cells in Crohn's patients with ATG16L1 polymorphisms [6]. Also, severe disruption of the unfolded protein response by selective deletion of Xbp1 in intestinal epithelial cells induces massive Paneth cell apoptosis and fulminant ileitis [8]. Third, germline and inducible gene deletion of the protein disulfide isomerase, anterior gradient 2, results in goblet cell mucin 2 deficiency [52•], expansion of the Paneth cell compartment, and severe terminal ileitis and colitis associated with induced endoplasmic reticulum stress [9•]. Collectively, these studies show that a diversity of genetic defects can disrupt Paneth cell homeostasis selectively with an associated ileitis that mimics human disease.
Additional experimental models of disease have provided evidence that Paneth cells contribute directly to the induction of inflammation. First, a mouse model of shock induced by systemic TNF-α administration was ameliorated when the cytokine was administered to IL-17R-null mice or when wild-type mice were treated with anti-IL-17A antibody [7]. Although IL-17A mainly is identified with activated Th17 cells, adoptive transfer experiments showed that the TNF-induced disorder was mediated by IL-17 from Paneth cell secretory granules and not by IL-17 of myeloid or Th17 cell origin [7]. In Atg16l1 hypomorphic mice (see above), genes involved in peroxisome proliferator-activated receptor pathways, adipocytokine signaling, and lipid metabolism were induced, and mRNA levels of serum amyloid A1, haptoglobin, and complement factors D and I were elevated in Paneth cells [6]. In particular, adipocytokines leptin and adiponectin mRNAs were among the most highly induced in Atg16l1-deficient Paneth cells [6]. These studies provide evidence that proinflammatory cytokines of Paneth cell origin, whether directly or indirectly, induce shock or alter enteric innate immunity in response to local or systemic infection or to immune stimulation.
Necrotizing enterocolitis (NEC) is a disease primarily affecting premature infants and is a leading cause of morbidity and mortality in neonatal intensive care units. A recent analysis of the LPS sensor TLR4/MD-2 receptor tandem in NEC patients provided evidence of a mucosal immunodeficiency in preterm neonates [53•]. Immunoreactive MD-2 protein was evident in healthy term neonates and adults, with Paneth cells being the only epithelial cells immunopositive for the coreceptors. In contrast, Paneth cells and lamina propria of premature infants and preterm infants with NEC were negative for MD-2 expression. A Paneth cell LPS sensing deficiency in the immature neonatal gut may predispose preterm newborns to NEC as bacterial consortia colonize the gut and expose it to microbe-associated danger signals [53•]. Perhaps, Paneth cell sensing of luminal bacteria helps to establish and maintain enteric homeostasis when the neonatal intestine is challenged by its first exposure to microbes.
Conclusion
The genetics and experimental models of Crohn's disease consistently reinforce the view that remarkably similar disease outcomes have diverse polygenic etiologies. The recent literature has identified varied genetic origins associated with disrupted Paneth cell homeostasis, induced Paneth cell endoplasmic reticulum stress, and increased sensitivity of the gut to proinflammatory stimuli. New mutations associated with the initiation of ileitis are certain to be found. As the spectrum of genetic variants that induce or predispose to inflammation becomes more complete, so will detailed mechanisms of Paneth cell involvement in NEC and IBD and the identification of corresponding therapeutic targets for intervention.
Acknowledgements
The author thanks Drs Hans Clevers, Calvin J. Kuo, and Edward Y. Skolnik for permission to adapt figures from their original, published reports for this article. The study is supported by NIH Grants DK044632 and AI059346.
References and recommended reading
Papers of particular interest, published within the annual period of review, have been highlighted as:
• of special interest
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Additional references related to this topic can also be found in the Current World Literature section in this issue (p. 656).
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Keywords:
endoplasmic reticulum stress; homeostasis; inflammation; microbiome; necrotizing enterocolitis
© 2010 Lippincott Williams & Wilkins, Inc.