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Paneth cell α-defensins in enteric innate immunity

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Abstract

Paneth cells at the base of small intestinal crypts of Lieberkühn secrete high levels of α-defensins in response to cholinergic and microbial stimuli. Paneth cell α-defensins are broad spectrum microbicides that function in the extracellular environment of the intestinal lumen, and they are responsible for the majority of secreted bactericidal peptide activity. Paneth cell α-defensins confer immunity to oral infection by Salmonella enterica serovar Typhimurium, and they are major determinants of the composition of the small intestinal microbiome. In addition to host defense molecules such as α-defensins, lysozyme, and Pla2g2a, Paneth cells also produce and release proinflammatory mediators as components of secretory granules. Disruption of Paneth cell homeostasis, with subsequent induction of endoplasmic reticulum stress, autophagy, or apoptosis, contributes to inflammation in diverse genetic and experimental mouse models.

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Abbreviations

AMP:

Antimicrobial peptide

CRIP:

Cysteine-rich intestinal polypeptide

Crp:

Cryptdin, a term applied only to mouse Paneth cell α-defensins

(6C/A)-Crp or (6C/A)-RMAD:

Peptides in which all Cys residues of the parent peptide are substituted with Ala to eliminate the disulfide array

CRS1C, CRS4C:

Two cysteine-rich sequence, α-defensin-related peptide families of mice

DEFA5-transgenic (+/+):

Mice transgenic for the human Paneth cell α-defensin HD5

ER:

Endoplasmic reticulum

HD5 and HD6:

Human defensin 5 and 6, the two human Paneth cell α-defensins

HNP:

Human neutrophil defensin

IL-17:

Interleukin-17

LL-37:

The human cathelicidin peptide

MMP7:

Matrix metalloproteinase-7

NK:

Natural killer cells

NMR:

Nuclear magnetic resonance

NP-:

Rabbit neutrophil α-defensin

proHD5:

The HD5 precursor

RegIII-γ:

Pancreatitis-associated protein 3 or regenerating islet-derived protein III-gamma

(R/K)-Crp or (R/K)-RMAD:

Peptides in which all Arg residue positions of the parent molecule are substituted with Lys

RMAD:

Rhesus myeloid α-defensin

RT-PCR:

Reverse transcriptase polymerase chain reaction

TNF-α:

Tumor necrosis factor-α

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Acknowledgments

Supported by NIH Grants DK044632 and AI059346.

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  1. Department of Pathology and Laboratory Medicine, Keck School of Medicine of the University of Southern California, USC/Norris Cancer Center, NRT 7505, 1450 Biggy Street, Los Angeles, CA, 90089-9601, USA

    André Joseph Ouellette

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Ouellette, A.J. Paneth cell α-defensins in enteric innate immunity. Cell. Mol. Life Sci. 68, 2215–2229 (2011). https://doi.org/10.1007/s00018-011-0714-6

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