The Paneth Cell: The Curator and Defender of the Immature Small Intestine

Abstract

Paneth cells were first described in the late 19th century by Gustav Schwalbe and Josef Paneth as columnar epithelial cells possessing prominent eosinophilic granules in their cytoplasm. Decades later there is continued interest in Paneth cells as they play an integral role in maintaining intestinal homeostasis and modulating the physiology of the small intestine and its associated microbial flora. Paneth cells are highly specialized secretory epithelial cells located in the small intestinal crypts of Lieberkühn. The dense granules produced by Paneth cells contain an abundance of antimicrobial peptides and immunomodulating proteins that function to regulate the composition of the intestinal flora. This in turn plays a significant role in secondary regulation of the host microvasculature, the normal injury and repair mechanisms of the intestinal epithelial layer, and the levels of intestinal inflammation. These critical functions may have even more importance in the immature intestine of premature infants. While Paneth cells begin to develop in the middle of human gestation, they do not become immune competent or reach their adult density until closer to term gestation. This leaves preterm infants deficient in normal Paneth cell biology during the greatest window of susceptibility to develop intestinal pathology such as necrotizing enterocolitis (NEC). As 10% of infants worldwide are currently born prematurely, there is a significant population of infants contending with an inadequate cohort of Paneth cells. Infants who have developed NEC have decreased Paneth cell numbers compared to age-matched controls, and ablation of murine Paneth cells results in a NEC-like phenotype suggesting again that Paneth cell function is critical to homeostasis to the immature intestine. This review will provide an up to date and comprehensive look at Paneth cell ontogeny, the impact Paneth cells have on the host-microbial axis in the immature intestine, and the repercussions of Paneth cell dysfunction or loss on injury and repair mechanisms in the immature gut.

Keywords: cathelicidin (LL37); cell death; defensins; immature intestine; necrotizing enterocolitis; paneth cell.

Figure 1

The intestinal epithelium. (Left) H&E stained ileum from P14 C57Bl6 mouse with vilus, crypt, and lamina propria labeled. (Right) Schematic of the intestinal epithelium, associated microbial flora, epithelial cell types (goblet cells, Paneth cells, enterocytes, and stem cells) intestinal microvasculature, and mucus layer. Corresponding labels for vilus, crypt, and lamina propria labeled are placed on the schematic to compare to the H&E stained section.

Figure 2

Intestinal epithelial cell differentiation pathways. The intestinal stem cell (ISC) differentiates into absorptive (enterocyte) or secretory precursors through Wnt/Notch signaling. While enterocytes further differentiate through HES-1 signaling, secretory lineages can differentiate into different cell types depending on conditions. Wnt signal pathways drive ISC differentiation into secretory precursor cells. Secretory precursors then develop either into enteroendocrine cells through Neurog3 signaling, or into goblet and Paneth cells following activation of Atoh1. Differentiation signal pathways to separate development of goblet cells and Paneth cells are still unknown. It is also important to note that recent data has shown that activation of ErbB3 acts as a suppressor of Atoh1, while genetic deletion of ErbB3 induces precocious development of Paneth cells.

Figure 3

Small intestinal AMP switch during intestinal development. During development, the immature intestine is protected by the AMP CRAMP (LL-37 in humans). However, CRAMP expression decreases around mid-development, at roughly the time that Paneth cells begin to develop. This “switch” occurs during mid-intestinal development which is around post-natal (P) day 10–21 in C57Bl6 mice and in the second trimester (between 20 and 28 weeks of gestation) in humans. In infants born prematurely, this switch is temporally similar to when extremely preterm infants are most susceptible to develop NEC (18).

Figure 4

Proposed role of the Paneth cell in development of NEC. As the immature intestine (A) is exposed to inflammation (B), oxygen radicals are produced creating a selective advantage for Proteobacteria sp. over obligate anaerobes such as the Firmicutes. This creates a feedback loop for sustaining and increasing the pro-inflammatory state in the immature intestine. Previous work from our lab has shown that intestinal inflammation can reduce intestinal mucus production and cause loss of Paneth cells (112, 129). (C) Loss of these important chemical and physical aspects of innate immunity allows bacteria to move from the mucus layer of the intestinal lumen and gain closer proximity to the epithelial surface, (D) followed eventually by attachment and invasion of the epithelium. (E) Once bacteria invade the intestinal tissue, further inflammation occurs including recruitment of leukocytes including neutrophils, macrophages, and monocytes (–135) which lead to eventual death of the tissues.