Abstract
ABSTRACTCrohn's disease (CD) is associated with delayed neutrophil recruitment and bacterial clearance at sites of acute inflammation as a result of impaired secretion of proinflammatory cytokines by macrophages. To investigate the impaired cytokine secretion and confirm our previous findings, we performed transcriptomic analysis in macrophages and identified a subgroup of individuals with CD who had low expression of the autophagy receptor optineurin (OPTN). We then clarified the role of OPTN deficiency in: macrophage cytokine secretion; mouse models of bacteria-driven colitis and peritonitis; and zebrafish Salmonella infection. OPTN-deficient bone-marrow-derived macrophages (BMDMs) stimulated with heat-killed Escherichia coli secreted less proinflammatory TNFα and IL6 cytokines despite similar gene transcription, which normalised with lysosomal and autophagy inhibitors, suggesting that TNFα is mis-trafficked to lysosomes via bafilomycin-A-dependent pathways in the absence of OPTN. OPTN-deficient mice were more susceptible to Citrobacter colitis and E. coli peritonitis, and showed reduced levels of proinflammatory TNFα in serum, diminished neutrophil recruitment to sites of acute inflammation and greater mortality, compared with wild-type mice. Optn-knockdown zebrafish infected with Salmonella also had higher mortality. OPTN plays a role in acute inflammation and neutrophil recruitment, potentially via defective macrophage proinflammatory cytokine secretion, which suggests that diminished OPTN expression in humans might increase the risk of developing CD.
Highlights
Crohn’s disease (CD) is a chronic relapsing inflammatory disorder, primarily affecting the gastrointestinal tract (Baumgart and Sandborn, 2012)
Mice lacking OPTN were significantly more susceptible to Citrobacter colitis and E. coli peritonitis owing to reduced neutrophil recruitment to sites of acute inflammation and impaired pro-inflammatory cytokine secretion
CD due to an innate immunodeficiency resulting from an impaired macrophage and neutrophil response might benefit from the use of lysosomal and autophagy modulators as a new therapeutic strategy in forthcoming clinical trials
Summary
Crohn’s disease (CD) is a chronic relapsing inflammatory disorder, primarily affecting the gastrointestinal tract (Baumgart and Sandborn, 2012). The impaired secretion of proinflammatory cytokines from macrophages upon bacterial stimulation (Smith et al, 2009; Sewell et al, 2012) could be responsible for this delay in neutrophil recruitment. This abnormal neutrophil response does not occur as a consequence of chronic inflammation: it was not seen in ulcerative colitis (UC) or rheumatoid arthritis (Segal and Loewi, 1976; Marks et al, 2006; Smith et al, 2009). Mutations in components of this oxidase that are damaging, but not severe enough to cause the oxidase to be seriously compromised, are associated with an increased incidence of early-onset CD (Dhillon et al, 2014)
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