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| Paneth cell | |
|---|---|
 Paneth cells, located at the base of the crypts of the small intestinal mucosa, and displaying bright red cytoplasmic granules. H&E stain. | |
| Details | |
| Location | Small intestineepithelium |
| Identifiers | |
| Latin | cellula panethensis |
| MeSH | D019879 |
| TH | H3.04.03.0.00017 |
| FMA | 62897 |
| Anatomical terms of microanatomy | |
Paneth cells are cells in the small intestineepithelium, alongsidegoblet cells,enterocytes, andenteroendocrine cells.[1] Some can also be found in thececum andappendix. They are located below the intestinal stem cells in theintestinal glands (also called crypts ofLieberkühn) and the largeeosinophilicrefractile granules that occupy most of theircytoplasm.
When exposed tobacteria or bacterialantigens, Paneth cells secrete several anti-microbial compounds (notablydefensins andlysozyme) that are known to be important in immunity and host-defense into thelumen of the intestinal gland, thereby contributing to maintenance of the gastrointestinal barrier by controlling the enteric bacteria. Therefore, Paneth cells play a role in theinnate immune system.
Paneth cells are named after 19th-century pathologistJoseph Paneth.
Paneth cells are found throughout thesmall intestine and the appendix at the base of theintestinal glands.[2] There is an increase in Paneth cell numbers towards the end of the small intestine.[3] Like the other epithelial cell lineages in the small intestine, Paneth cells originate at the stem cell region near the bottom of the gland.[4] There are on average 5–12 Paneth cells in each small intestinal crypt.[5]
Unlike the other epithelial cell types, Paneth cells migrate downward from the stem cell region and settle just adjacent to it.[4] This close relationship to the stem cell region suggests that Paneth cells are important in defending the gland stem cells from microbial damage,[4] although their function is not entirely known.[2] Furthermore, among the four aforementioned intestinal cell lineages, Paneth cells live the longest (approximately 57 days).[6]
Paneth cells secrete antimicrobial peptides and proteins, which are "key mediators of host-microbe interactions, including homeostatic balance with colonizing microbiota and innate immune protection from enteric pathogens."[7]
Small intestinal crypts housestem cells that serve to constantly replenishepithelial cells that die and are lost from thevilli.[7] Paneth cells support the physical barrier of the epithelium by providing essential niche signals to their neighboringintestinal stem cells. Protection and stimulation of thesestem cells is essential for long-term maintenance of the intestinalepithelium, in which Paneth cells play a critical role.[8]
Paneth cells displaymerocrine secretion, that is, secretion viaexocytosis.[9]
Paneth cells are stimulated to secretedefensins when exposed to bacteria (bothGram positive andGram-negative types), or such bacterial products aslipopolysaccharide,lipoteichoic acid,muramyl dipeptide andlipid A.[10] They are also stimulated bycholinergic signaling normally preceding the arrival of food which potentially may contain a new bacterial load.[10]
Paneth cells sense bacteria viaMyD88-dependenttoll-like receptor (TLR) activation which then triggers antimicrobial action.[11] For example, research showed that in the secretory granules, murine and human Paneth cells express high levels ofTLR9. TLR9 react toCpG-ODN and unmethylated oligonucleotides,pathogen-associated molecular patterns (PAMPs) typical for bacterial DNA. Internalizing these PAMPs and activating TLR9 leads todegranulation and release of antimicrobial peptides and other secretions.[12] Surprisingly, murine Paneth cells do not express mRNA transcripts forTLR4.[5]
The principal defense molecules secreted by Paneth cells arealpha-defensins, which are known ascryptdins in mice.[13] Thesepeptides havehydrophobic and positively charged domains that can interact withphospholipids incell membranes. This structure allows defensins to insert into membranes, where they interact with one another to form pores that disrupt membrane function, leading to cell lysis. Due to the higher concentration of negatively chargedphospholipids in bacterial than vertebratecell membranes, defensins preferentially bind to and disrupt bacterial cells, sparing the cells they are functioning to protect.[14]
Human Paneth cells produce two α-defensins known ashuman α-defensin HD-5 (DEFA5) andHD-6 (DEFA6).[15] HD-5 has a wide spectrum of killing activity against both Gram positive and Gram negative bacteria as well as fungi (Listeria monocytogenes,Escherichia coli,Salmonella typhimurium, and Candida albicans).[5] The antimicrobial activity of HD-6 consists of self-assembling into extracellular nets that entrap bacteria in the intestine and thereby preventing their translocation across the epithelial barrier.[16]
Human Paneth cells also produce other AMPs includinglysozyme, secretoryphospholipase A2, andregenerating islet-derived protein IIIA.[17] Lysozyme is anantimicrobial enzyme that dissolves the cell walls of many bacteria, and phospholipase A2 is an enzyme specialized in the lysis of bacterialphospholipids .[10] This battery of secretory molecules gives Paneth cells a potent arsenal against a broad spectrum of agents, including bacteria,fungi and even some envelopedviruses.[18]
During conventional protein secretion, proteins are transported through theER-Golgi complex packaged in secretory granules and released to the extracellular space. Should invasive pathogens disrupt theGolgi apparatus, causing an impairment in the Paneth cell secretion of antimicrobial proteins, an alternative secretion pathway exists: it has been shown thatlysozyme can be rerouted through secretoryautophagy. In secretory autophagy, cargo is transported in an LC3+ vesicle and discharged at theplasma membrane, thus bypassing theER-Golgi complex. Not all bacteria prompts secretory autophagy: commensal bacteria, for example, does not cause Golgi breakdown and therefore does not trigger the secretory autophagy oflysozyme. A dysfunction in secretory autophagy is thought to be a possible contributing factor to Crohn's disease.[19]
Paneth cells maintain the health of the intestine by acting asmacrophages; it has been shown that Paneth cells clear dying cells via apoptotic cell uptake. The phagocytic function of Paneth cells was discovered using a series of experiments, one of which made use of mice that were radiated with a low dose Cesium-137 (137Cs), mimicking chemotherapy undergone by cancer patients.[20] These findings may be significant for addressing the side effects suffered by cancer patient whose intestinal health is damaged by chemotherapy: approximately 40% of all cancer therapy patients experience gastrointestinal (GI)mucositis during their treatment, with the number jumping to 80% in patients receiving abdominal or pelvicirradiation.[21]
Paneth cells participate in theWnt signaling pathway andNotch signalling pathway, which regulate proliferation of intestinal stem cells andenterocytes necessary for epithelium cell renewal. They express the canonical Wnt ligands:Wnt3a,Wnt9b, andWnt11, which bind toFrizzled receptors on intestinal stem cells to driveβ-catenin/Tcf signaling. Paneth cells are also a major source of Notch ligandsDLL1 andDLL4, binding to Notch receptorsNotch1 andNotch2 on intestinal stem cells andenterocyte progenitors.[8]
Recently, however, it has been discovered that the regenerative potential of intestinal epithelial cells declines over time as a result of aged Paneth cells secreting the proteinNotum, which is an extracellular inhibitor of Wnt signaling. If Notum secretion is inhibited, the regenerative potential of the intestinal epithelium could increase.[22]
It has been established thatzinc is essential for the function of Paneth cells. A defect in the Zn transporter (ZnT)2 impairs Paneth cell function by causing uncoordinated granule secretion. Mice lacking the (ZnT)2 transporter not only exhibit impaired granule secretion, they also suffer from increased inflammatory response to lipopolysaccharide and are less capable of bactericidal activity.[23] Normally,zinc is stored in the secretory granules and, upon degranulation, is released in the lumen. It has been speculated that the storage of heavy metals contributes to direct antimicrobial toxicity, as Zn is released upon cholinergic PC stimulation.[24]
Zinc deficiency is also implicated in alcohol‐induced Paneth cell α‐defensin dysfunction, which contributes to alcohol-relatedsteatohepatitis. Zinc can stabilize human α‐defensin 5 (HD5), which is responsible for microbiome homeostasis. In line with this, the administration of HD5 can effectively alter the microbiome (especially by increasingAkkermansia muciniphila), and reverse the damage inflicted on the microbiome by excessive alcohol consumption. Dietary zinc deficiency on the other hand exacerbates the deleterious effect of alcohol on the bactericidal activity of Paneth cells.[25]
Abnormal Paneth cells with reduced expression or secretion of defensins HD-5 and HD-6 (in human) and antimicrobial peptides are associated withinflammatory bowel disease.[26][17] In addition to that, several of theCrohn's disease-risk alleles are associated with Paneth cell dysfunction are involved in processes such asautophagy, theunfolded protein response, and the regulation ofmitochondrial function.[17]
It is believed that the dysfunction of Paneth cells compromises antimicrobial peptides leading to amicrobiota composition shift, and even dysbiosis.[27]Crohn's disease patients with a higher percentage of abnormal Paneth cells showed significantly reduced bacterial diversity compared with patients with a lower percentage of abnormal Paneth cells, reflecting a reduced abundance of anti-inflammatory microbes.[28] Collectively, these findings support the theory that Paneth cell dysfunction may lead to a dysbiotic microbiota that, in turn, could predispose an individual to the development of Crohn's disease.[17] However, it is yet to be established whether Paneth cell dysfunction is the cause of dysbiosis, or its concomitant effect.[27]
Paneth cells develop gradually during gestation and therefore preterm babies might not have them in sufficient numbers. This leaves preterm babies vulnerable tonecrotizing enterocolitis. About mid-way though the development of the small intestine,cathelicidin secretion is replaced by α-defensin secretion.[29] The small intestine of the premature baby is at this transition stage when the baby is born, making preterm babies susceptible to intestinal injury and, subsequently, tonecrotizing enterocolitis.[18] It should furthermore be noted that early Paneth cells do not possess fully functional, mature granules.[30]
The mechanism that links Paneth cells tonecrotizing enterocolitis remains unclear, but it has been theorized that a bloom ofProteobacteria and, more specifically,Enterobacteriaceae species precedes the development of the condition.[31] When an inflammation then subsequently occurs, nitrates can be fermented byEnterobacteriaceae sp. but not by obligate anaerobes, which cannot use nitrates as a growth substrate. Thus,Proteobacteria are able to use this selective pressure to out-compete the obligate anaerobicFirmicutes andBacteroidetes, resulting in their overgrowth and consequent dysbiosis.[18]
The process is thought to begin when the premature infant is exposed to foreign antigens via formula feeding. Inflammatory cytokines are subsequently released, creating a more aerobic state leading to a competitive advantage forProteobacteria. As the microbiome becomes more dysbiotic, anti-inflammatory mechanisms weaken, which contributes to a cycle of increasing intestinal inflammation. The inflammation leads to a further loss in Paneth cells density and function, resulting in the impairment of AMP secretion and the destruction of the stem cell niche.[18]
Whereas the role of Paneth cells in irritable bowel syndrome and Crohn's disease has received ample attention,[32][17] relatively little is known about the effect Panth cell impairment has on the pathogenesis ofnon-alcoholic steato-hepatitis ornon-alcoholic fatty liver disease.
Murine models indicate that obesity may decrease the secretion ofα-defensin from Paneth cells, leading todysbiosis.[33] and at least one murine model suggests that when α-defensin levels in the intestinal lumen are restored by intravenous administration ofR-Spondin1 to induce Paneth cell regeneration, liver fibrosis is ameliorated as a result of the dysbiosis resolving. It is hypothesized that selective microbicidal activities, as well as increasing Muribaculaceae and decreasingHarryflintia, contribute to amelioration in fibrogenesis.[34]
One study described the injection ofdithizone, which can disrupt cell granulates, into mice that were fed a high-fat diet in order to identify Paneth-cell-oriented microbial alterations. The application ofdithizone improved high-fat diet glucose intolerance and insulin resistance and was associated with an alleviation in the severity of liver steatosis in HFD mice, possibly through gut microbiome modulation involving the increase inBacteroides. It has therefore been suggested that microbiome-targeted therapies may have a role in the treatment of non-alcoholic fatty liver disease.[35]
Further research is needed to elucidate the connection between Paneth cells and the gut-liver-axis.