Paneth cells are cells in the small intestine epithelium, alongside goblet cells, enterocytes, and enteroendocrine cells. Some can also be found in the cecum and appendix. They lie interspersed between intestinal stem cells in the intestinal glands (also called crypts of Lieberkühn) and under the large eosinophilic refractile granules that occupy most of their cytoplasm. 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 small intestine and the appendix at the base of the intestinal glands. There is an increase in Paneth cell numbers towards the end of the small intestine. Like the other epithelial cell lineages in the small intestine, Paneth cells originate at the stem cell region near the bottom of the gland. There are on average 5–12 Paneth cells in each small intestinal crypt. Unlike the other epithelial cell types, Paneth cells migrate downward from the stem cell region and settle just adjacent to it. This close relationship to the stem cell region suggests that Paneth cells are important in defending the gland stem cells from microbial damage, although their function is not entirely known. Furthermore, among the four aforementioned intestinal cell lineages, Paneth cells live the longest (approximately 57 days).
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." Small intestinal crypts house stem cells that serve to constantly replenish epithelial cells that die and are lost from the villi. Paneth cells support the physical barrier of the epithelium by providing essential niche signals to their neighboring intestinal stem cells. Protection and stimulation of these stem cells is essential for long-term maintenance of the intestinal epithelium, in which Paneth cells play a critical role. Paneth cells display merocrine secretion, that is, secretion via exocytosis.
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. They are also stimulated by cholinergic signaling normally preceding the arrival of food which potentially may contain a new bacterial load. Paneth cells sense bacteria via MyD88-dependent toll-like receptor (TLR) activation which then triggers antimicrobial action. 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. Surprisingly, murine Paneth cells do not express mRNA transcripts for TLR4.
Antimicrobial secretions The principal defense molecules secreted by Paneth cells are alpha-defensins, which are known as cryptdins in mice. These peptides have hydrophobic and positively charged domains that can interact with phospholipids in cell 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 charged phospholipids in bacterial than vertebrate cell membranes, defensins preferentially bind to and disrupt bacterial cells, sparing the cells they are functioning to protect. Human Paneth cells produce two α-defensins known as human α-defensin HD-5 (DEFA5) and HD-6 (DEFA6). 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). 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. Human Paneth cells also produce other AMPs including lysozyme, secretory phospholipase A2, and regenerating islet-derived protein IIIA. Lysozyme is an antimicrobial enzyme that dissolves the cell walls of many bacteria, and phospholipase A2 is an enzyme specialized in the lysis of bacterial phospholipids . This battery of secretory molecules gives Paneth cells a potent arsenal against a broad spectrum of agents, including bacteria, fungi and even some enveloped viruses.
Secretory autophagy During conventional protein secretion, proteins are transported through the ER-Golgi complex packaged in secretory granules and released to the extracellular space. Should invasive pathogens disrupt the Golgi apparatus, causing an impairment in the Paneth cell secretion of antimicrobial proteins, an alternative secretion pathway exists: it has been shown that lysozyme can be rerouted through secretory autophagy. In secretory autophagy, cargo is transported in an LC3+ vesicle and discharged at the plasma membrane, thus bypassing the ER-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 of lysozyme. A dysfunction in secretory autophagy is thought to be a possible contributing factor to Crohn's disease.
… excerpt ends here. Continue reading the full article.
