Paneth cell
This article needs more primary sources. (April 2020) |
Paneth cell | |
---|---|
Details | |
Location | Small intestine epithelium |
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 intestine
.When exposed to bacteria or bacterial antigens, Paneth cells secrete several anti-microbial compounds (notably defensins and lysozyme) that are known to be important in immunity and host-defense into the lumen of the intestinal gland, thereby contributing to maintenance of the gastrointestinal barrier by controlling the enteric bacteria. Therefore, Paneth cells play a role in the innate immune system.
Paneth cells are named after 19th-century pathologist Joseph Paneth.
Structure
Paneth cells are found throughout the
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]
Function
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 house
Paneth cells display merocrine secretion, that is, secretion via exocytosis.[9]
Sensing microbiota
Paneth cells are stimulated to secrete defensins when exposed to bacteria (both Gram positive and Gram-negative types), or such bacterial products as lipopolysaccharide, lipoteichoic acid, muramyl dipeptide and lipid A.[10] They are also stimulated by cholinergic signaling normally preceding the arrival of food which potentially may contain a new bacterial load.[10]
Paneth cells sense bacteria via MyD88-dependent toll-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 of TLR9. TLR9 react to CpG-ODN and unmethylated oligonucleotides, pathogen-associated molecular patterns (PAMPs) typical for bacterial DNA. Internalizing these PAMPs and activating TLR9 leads to degranulation and release of antimicrobial peptides and other secretions.[12] Surprisingly, murine Paneth cells do not express mRNA transcripts for TLR4.[5]
Antimicrobial secretions
The principal defense molecules secreted by Paneth cells are
Human Paneth cells produce two α-defensins known as human α-defensin HD-5 (DEFA5) and HD-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 including
Secretory autophagy
During conventional protein secretion, proteins are transported through the
Phagocytic function
Paneth cells maintain the health of the intestine by acting as macrophages; 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 pelvic irradiation.[21]
Epithelium maintenance
Paneth cells participate in the Wnt signaling pathway and Notch signalling pathway, which regulate proliferation of intestinal stem cells and enterocytes necessary for epithelium cell renewal. They express the canonical Wnt ligands: Wnt3a, Wnt9b, and Wnt11, which bind to Frizzled receptors on intestinal stem cells to drive β-catenin/Tcf signaling. Paneth cells are also a major source of Notch ligands DLL1 and DLL4, binding to Notch receptors Notch1 and Notch2 on intestinal stem cells and enterocyte 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 protein Notum, which is an extracellular inhibitor of Wnt signaling. If Notum secretion is inhibited, the regenerative potential of the intestinal epithelium could increase.[22]
Zinc
It has been established that zinc 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-related steatohepatitis. 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 increasing Akkermansia 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]
Clinical significance
Abnormal Paneth cells with reduced expression or secretion of defensins HD-5 and HD-6 (in human) and antimicrobial peptides are associated with inflammatory bowel disease.[26][17] In addition to that, several of the Crohn's disease-risk alleles are associated with Paneth cell dysfunction are involved in processes such as autophagy, the unfolded protein response, and the regulation of mitochondrial function.[17]
It is believed that the dysfunction of Paneth cells compromises antimicrobial peptides leading to a microbiota 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]
Necrotizing enterocolitis
Paneth cells develop gradually during gestation and therefore preterm babies might not have them in sufficient numbers. This leaves preterm babies vulnerable to
The mechanism that links Paneth cells to
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 for
Non-alcoholic fatty liver disease
Whereas the role of Paneth cells in irritable bowel syndrome and Crohn's disease has received ample attention,
Murine models indicate that obesity may decrease the secretion of α-defensin from Paneth cells, leading to dysbiosis.[33] and at least one murine model suggests that when α-defensin levels in the intestinal lumen are restored by intravenous administration of R-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 decreasing Harryflintia, contribute to amelioration in fibrogenesis.[34]
One study described the injection of dithizone, 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 of dithizone 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 in Bacteroides. 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.
See also
- List of human cell types derived from the germ layers
- List of distinct cell types in the adult human body
References
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- ^ a b "Paneth's cell | anatomy". Britannica.com. Retrieved 2016-09-17.
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