Conclusion and Future Perspectives

Macrophages and Paneth cells, both of which are critical for mucosal immunity in the intestine, are two of the newest cell types in which autophagy genes have been associated with unique cell type-specific roles (Fig. 3). Other chapters in this volume discuss the essential roles of the autophagy pathway in the biology of additional cell types implicated in intestinal inflammation, including lymphocytes and

Crohn Disease Model
  1. 3 Mutation of autophagy genes leads to striking abnormalities in key cell types implicated in intestinal inflammation. Macrophages serve a critical role in mucosal immunity by secreting cytokines and other regulatory molecules that shape the immune environment. Macrophages can also phagocytose and destroy bacteria that inappropriately penetrate the epithelial wall. In addition to a failure to control intracellular bacterial replication through classical autophagy (reviewed in other chapters), autophagy mutant macrophages produce increased amounts of reactive oxygen species (ROS) and the proinflammatory cytokines IL-ip and IL-18 (Saitoh et al. 2008). Paneth cells are highly specialized intestinal epithelial cells located at the crypt base. Paneth cells package antimicrobial factors in granules and, upon stimulation, secrete the granule contents into the intestinal lumen. In autophagy mutant Paneth cells, organelle degeneration is accompanied by granule morphology and secretion abnormalities (Cadwell et al. 2008a, b). Moreover, mutant Paneth cells display a gain-of-function overproduction of inflammatory proteins. Importantly, these changes are also observed in human Crohn's disease patients that are homozygous for the ATG16L1 risk polymorphism
  2. 3 Mutation of autophagy genes leads to striking abnormalities in key cell types implicated in intestinal inflammation. Macrophages serve a critical role in mucosal immunity by secreting cytokines and other regulatory molecules that shape the immune environment. Macrophages can also phagocytose and destroy bacteria that inappropriately penetrate the epithelial wall. In addition to a failure to control intracellular bacterial replication through classical autophagy (reviewed in other chapters), autophagy mutant macrophages produce increased amounts of reactive oxygen species (ROS) and the proinflammatory cytokines IL-ip and IL-18 (Saitoh et al. 2008). Paneth cells are highly specialized intestinal epithelial cells located at the crypt base. Paneth cells package antimicrobial factors in granules and, upon stimulation, secrete the granule contents into the intestinal lumen. In autophagy mutant Paneth cells, organelle degeneration is accompanied by granule morphology and secretion abnormalities (Cadwell et al. 2008a, b). Moreover, mutant Paneth cells display a gain-of-function overproduction of inflammatory proteins. Importantly, these changes are also observed in human Crohn's disease patients that are homozygous for the ATG16L1 risk polymorphism dendritic cells. Thus, a major challenge facing disease research is to discriminate those functions of autophagy that are critical for inflammatory bowel disease patho-genesis from functions of autophagy that may be important in other circumstances. Although the role of autophagy genes in the Paneth cell is the only one validated with Crohn's disease specimens to date, it is reasonable to speculate that autophagy contributes to Crohn's disease pathogenesis through multiple cell type-specific mechanisms that are not mutually exclusive.

Rarely are specific pathological hallmarks of a complicated human disease associated with a specific genetic polymorphism observed in a model organism. Perhaps this is not surprising for a disease like Crohn's disease in which many genetic polymorphisms, and likely environmental factors, act in concert to produce a complex pathologic picture that may vary from person to person. It is fascinating that the two Atg16L1--deficient and the two Nod2-deficient mutant mouse models all display aberrant production of inflammatory signals, although the mechanisms responsible may be quite distinct. With our current knowledge, there is no obvious unifying mechanism by which the autophagosome, or autophagosome-mediated clearance of intracellular bacteria, could be involved in all of the observed cell type-specific effects of Atg16L1 deficiency in macrophages and Paneth cells. Overproduction of IL-1P and IL-18 in response to LPS was not accompanied by an increase in autophagosome formation (Saitoh et al. 2008). Also, Paneth cell abnormalities in Atg16L1HM mice arise in the absence of exogenous bacterial challenge, and these mice do not exhibit increased sensitivity to oral L. monocytogenes challenge (Cadwell et al. 2008a), a clear distinction from the Nod2 KO mice. Although autophagosomes could be involved in recycling organelles in Paneth cells, autophagosome formation has not previously been associated with transcriptional changes, such as those observed in Atg16L1 -deficient Paneth cells. The observation that Atg16L1 or Atg5-deficient thymocytes display none of the transcriptional features associated with the aberrant Paneth cells further supports the need for in vivo and cell type-specific studies to define the mechanisms responsible for these seemingly disparate consequences of autophagy protein deficiency. While investigators examine the role of the autophagy pathway in complicated diseases such as Crohn's, these studies indicate that there is yet much to learn about the autophagy proteins themselves.

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