Interplay of autophagy and innate immunity in Crohn's disease: a key immunobiologic feature

Abstract

Crohn's disease representing a clinical phenotype of inflammatory bowel disease is a polygenic immune disorder with complex multifactor etiology. Recent genome-wide association studies of susceptibility loci have highlighted on the importance of the autophagy pathway, which previously had not been implicated in disease pathology. Autophagy represents an evolutionarily highly conserved multi-step process of cellular self-digestion due to sequestration of excessive, damaged, or aged proteins and intracellular organelles in double-membranous vesicles of autophagosomes, terminally self-digested in lysosomes. Autophagy is deeply involved in regulation of cell development and differentiation, survival and senescence, and it also fundamentally affects the inflammatory pathways, as well as the innate and adaptive arms of immune responses. Autophagy is mainly activated due to sensors of the innate immunity, i.e., by pattern recognition receptor signaling. The interplay of genes regulating immune functions is strongly influenced by the environment, especially gut resident microbiota. The basic challenge for intestinal immune recognition is the requirement of a simultaneous delicate balance between tolerance and responsiveness towards microbes. On the basis of autophagy-related risk genetic polymorphisms (ATG16L1, IRGM, NOD2, XBP1) impaired sensing and handling of intracellular bacteria by innate immunity, closely interrelated with the autophagic and unfolded protein pathways seem to be the most relevant immunobiologic events. Autophagy is now widely considered as a key regulator mechanism with the capacity to integrate several aspects of Crohn's disease pathogenesis. In this review, recent advances in the exciting crosstalk of susceptibility coding variants-related autophagy and innate immunity are discussed.

Keywords: Autophagy; Autophagy genes; Crohn's disease; Gut microbiota; Innate immunity.

Figure 1

The autophagic process and types of autophagy.

Figure 2

Schematic illustration of the crosstalk between autophagy and innate immunity in Crohn’s disease. PAMP: Pathogen-associated molecular patterns; DAMP: Damage-associated molecular pattern; ER: Endoplasmic reticulum; UPR: Unfolded protein response; NOD: Nucleotide-binding oligomerization domain-containing protein; MDP: N-acetyl-muramyl-peptide; LPS: Lipopolysaccharide; TLR: Toll-like receptor; XBP1: X-box binding protein 1; IRGM: Immunity-related GTPase family M protein.