Abstract
BackgroundEnteric antimicrobial peptides secreted from Paneth cells, including α-defensins (in mice named cryptdins), are key effector molecules of innate immunity in the small intestine. The importance of Paneth cells α-defensins emerged from studies of enteric bacterial infection in genetically modified mice, as well as from recent studies linking reduced levels of these α-defensins to Crohn's disease localized to the ileum. However, analysis of expression of Paneth cell α-defensins is incomplete. We therefore performed a comprehensive evaluation of the distribution of antimicrobial molecules along the mouse small intestinal tract to identify potential variations in regional expression.ResultsIn conventionally reared mice, the repertoire of Paneth cell antimicrobials differs between duodenum and ileum. In contrast to the uniform expression of most Paneth cell antimicrobials, both cryptdin 4 and cryptdin-related sequences (CRS) 4C peptides were expressed at progressively increasing amounts (101- and 104-fold, respectively) comparing duodenum and ileum. In tissues other than the small intestine, expression of CRS peptides was noted in thymus and caecum. Most Paneth cell products were also produced in the small intestine of germ-free mice at levels similar to those in controls, however CRS4C and RegIIIγ had reduced levels in the former (3- and 8-fold, respectively). No significant changes in expression levels of Paneth cell antimicrobial peptides was observed after oral challenge with either Salmonella enterica serovar typhimurium or Listeria monocytogenes, supporting current notions on the constitutive nature of this defensive system.ConclusionThe repertoire of antimicrobial peptides changes along the small intestinal tract, and a subset of these molecules are up-regulated upon colonization, but not in response to enteric bacterial pathogens. The changes detected upon colonization suggest that Paneth cell antimicrobial peptides may play an important role in commensal microbial homeostasis, in addition to their proposed role in protection against infection. In addition, the differential expression of CRS4C along the small intestine suggests mechanisms of regulation that are distinct from other Paneth cell derived antimicrobial peptides.
Highlights
IntroductionEnteric antimicrobial peptides secreted from Paneth cells, including α-defensins (in mice named cryptdins), are key effector molecules of innate immunity in the small intestine
Enteric antimicrobial peptides secreted from Paneth cells, including α-defensins, are key effector molecules of innate immunity in the small intestine
Many important antibacterial components, such as α-defensins, lysozyme, phospholipase A2 and the C-type lectin regenerating islet-derived gamma (RegIIIγ) are produced at high levels and stored in Paneth cell granules [3,4]
Summary
Enteric antimicrobial peptides secreted from Paneth cells, including α-defensins (in mice named cryptdins), are key effector molecules of innate immunity in the small intestine. The gastrointestinal epithelium is continuously exposed to high numbers of bacteria, including the resident microbiota as well as to foreign bacteria. Despite this high bacterial exposure, infections are rare, which suggests highly efficient mechanisms both to protect the host and to maintain a host-microbe balance. Many important antibacterial components, such as α-defensins (cryptdins in mice), lysozyme, phospholipase A2 and the C-type lectin RegIIIγ are produced at high levels and stored in Paneth cell granules [3,4]. The cell specific regulation of Paneth cell α-defensins has partly been unravelled with the recent identification of the transcription factor TCF-4 being a key protein [7,8]
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