Several old and new observations suggest the existence in Crohn's disease of a phagocytic disorder of macrophages related to impaired bactericidal activity of host cells or to the presence of invasive bacteria that have developed strategies to counteract macrophage killing. It was recently reported that disordered macrophage cytokine secretion underlies impaired acute inflammation and bacterial clearance in Crohn's disease. Secretion of proinflammatory cytokines by CD macrophages was impaired in response to E. coli or specific Toll-like receptor agonists. In addition, major advances in the etiology of Crohn's disease came from the existence of polymorphism in NOD2 and autophagy-related susceptibility genes (ATG16L1 and IRGM) in patients and from the identification of the presence of adherent-invasive E. coli (AIEC) colonizing the CD ileal mucosa and able to resist to macrophage killing. The role of impaired autophagy in Crohn's disease patients has been recently reinforced by the observation that the peptidoglycan receptor NOD2, in addition to sense intracellular bacteria, can induce autophagy by recruiting the critical autophagy protein ATG16L1 to the plasma membrane during bacterial internalization. Defects in autophagy might be the key element of the pathogenic pathway that lead to defective microbial killing, increased exposure to commensal and pathogenic intestinal bacteria and T cell activation. Defects in Paneth cells secreting lysozyme and antimicrobial peptides are observed in patients with ATG16L1 risk allele. Thus, the induction of autophagy or administration of preparations that mirrors the secretion of Paneth cells or both may be regarded as new therapeutic avenues for the treatment of Crohn's disease.
