Autophagy-Mediated Innate Defense Mechanism in Crypt Paneth Cells Responding To Impairment of Small Intestine Barrier after Total-Body Gamma-Photon Irradiation

Nikolai V. Gorbunov
The Henry M. Jackson Foundation for the Advancement of Military Medicine, Inc., Bethesda, MD, USA

Juliann G. Kiang

Series: Cell Biology Research Progress
BISAC: SCI017000

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Volume 10

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Special issue: Resilience in breaking the cycle of children’s environmental health disparities
Edited by I Leslie Rubin, Robert J Geller, Abby Mutic, Benjamin A Gitterman, Nathan Mutic, Wayne Garfinkel, Claire D Coles, Kurt Martinuzzi, and Joav Merrick

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Macroautophagy (mATG) is a major lysosomal mechanism for the bulk degradation of cytoplasmic constituents, including proteins, damaged organelles, and penetrated pathogens. It is characterized by sequestration of entire portions of the cytoplasm by a double-membrane bounded vacuole called autophagosome. Despite its action as a self-digestion process, autophagy is mainly considered to be a well-regulated pathway to provide cell survival and remodeling. A line of evidence indicates that mATG plays a crucial role in both innate and adaptive immunity. It has been shown that mATG can suppress viral infections, inactivate intracellular bacteria and parasites, and deliver cytoplasmic antigens for MHC class II presentation to the adaptive immune system.

Thus, the immune system utilizes mATG for degradation of cytoplasmic materials, to both restrict intracellular pathogens and regulate adaptive immunity. Exposure to cytotoxic agents often interferes with this cross-talk, impairs immune system, and compromises host barrier functions that can ultimately lead to pathogen translocation and sepsis. Very little is known on the role of mATG in the innate mechanisms emerging to compensate immune homeostasis under the immunosuppressive conditions. This chapter is focused on role of mATG in the innate defense mechanism activated in intestinal crypt Paneth cells following acute ionizing irradiation.

Total-body acute ionizing irradiation either due to accidental exposure or radiotherapy of malignant diseases is associated with life-threatening effects where severity of outcomes is predominantly determined by impairment of dose-limiting immune tissue and small intestine. Thus, radiation exposure can induce death of radio-sensitive proliferating crypt epithelial precursor cells and cells of the gut-associated lymphoid tissue (GALT) that compromise integrity of the intestinal mucosal barrier, increase probability of bacterial translocation from the gut lumen and sepsis. Recent data demonstrate important role of Paneth cells in innate defense mechanisms of intestinal mucosa. Paneth cells are located at the base of the crypts of Lieberk¨¹hn adjacent to and/or surrounding the multi-potent crypt stem cells. They represent a relatively stable population of long-lived, radio-resistant, and differentiated cells.

Paneth cells secrete several bacteriolytic enzymes and antimicrobial peptides into the intestinal lumen to suppress bacterial translocation. Among the secreted peptides are ¦Á-defensins, cationic peptides with a broad spectrum of antimicrobial activity and the ability to rapidly galvanize antigen-presenting cells, activate adaptive immune responses, and interfere with pro-inflammatory cytokines. Herein, we show that radiation-induced systemic immuno-suppression and damage to intestinal mucosa can promote bacterial translocation from gut lumen to crypt lumen. That is correlated with mATG up-regulation and mATG-mediated secretary activity of crypt Paneth cells. We suggest that effective countermeasures against radiation injury shall include therapeutic modulation of mATG activity in intestinal Paneth cells. (Imprint: Nova)

1. Introduction

2. Hypothesis Test: Experimental Procedures and Technical Approach

3. Effects of Whole-Body Ionizing Irradiation

3.1. Acute Hematopoietic Effect

3.2. Alterations in the Crypt/Villus Structures Induced by Ionizing Irradiation

3.3. Upregulation of Autophagy in Small Intestine of Irradiated Mice

3.4. Expression of ¦Á-Defensin-4 in Small Intestine of Irradiated Mice

4. Conclusion

5. Perspective

6. References

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