Crohn's disease (CD) is a complex and highly heterogeneous chronic inflammatory disorder, primarily affecting the gastrointestinal tract. Genetic and functional studies have highlighted a key role for innate immunity in its pathogenesis. Profound systemic defects in innate immunity and acute inflammation are understood to result in markedly delayed clearance of bacteria from the tissues, leading to local chronic granulomatous inflammation and compensatory adaptive immunological changes. Macrophages, key orchestrators of acute inflammation, are likely to play an important role in the initial impaired innate immune response. Monocyte-derived macrophages from CD patients stimulated with Escherichia coli were shown to release attenuated levels of tumour necrosis factor and interferon-γ with normal secretion of interleukin-8 (IL-8), IL-10 and IL-6. In controls, the secretion of these cytokines was strongly positively correlated, which was not seen with CD macrophages. The transcriptomes of CD and control macrophages were examined in an attempt to understand the molecular basis of this defect. There were no differentially expressed genes identified between the two groups, consistent with genetic heterogeneity; however, a number of molecules were found to be under-expressed in subgroups of CD patients. The most common of these was optineurin (OPTN) which was under-expressed in approximately 10% of the CD patients. Reduced OPTN expression coincided with lower intracellular protein levels and diminished cytokine secretion after bacterial stimulation both in the patients and with small interfering RNA knockdown in THP-1 cells. Identifying and studying subgroups of patients with shared defective gene expression could aid our understanding of the mechanisms underlying highly heterogeneous diseases such as CD.

Crohn'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.

There has been an explosion of literature in recent years highlighting the pivotal role of matrix metalloproteases (MMPs) in the immune response. This review will focus on our current understanding of MMPs in the gastrointestinal tract and in particular the field of inflammatory bowel disease. MMPs are structurally similar proteins that classically degrade extracellular components. In the gastrointestinal tract, they are involved in the physical maintenance and turnover of the intestinal barrier, aid in leukocyte recruitment, regulate the activity of cytokines, chemokines, and growth factors. During inflammation, numerous MMPs are upregulated in the bowel and play a key role in the resolution of inflammation and wound healing during the normal immune response. In humans, an aberrant expression has been extensively documented in inflammatory bowel disease implicating them in tissue degradation, persistence of the inflammatory state and fibrosis. Animal studies in particular knockout mouse models have provided insight into the importance of individual MMPs in bowel homeostasis and inflammation. Endogenous inhibitors of MMPs such as tissue inhibitors of MMPs (TIMPs) and alpha-2 macroglobulin maintain the balance between extracellular matrix deposition and degradation. An imbalance between MMPs and their inhibitors through genetic variation, gene expression abnormalities, or environmental effects can directly impact on tissue homeostasis resulting in tissue damage and prolonged inflammation. In the future, targeting MMPs or their inhibitors could be a possible therapeutic option. The challenge will be achieving selectivity.

Background and Aims:ADAM [A Disintegrin And Metalloproteinase] is a family of peptidase proteins which have diverse roles in tissue homeostasis and immunity. Here, we study ADAM-like DECysin-1 [ADAMDEC1] a unique member of the ADAM family. ADAMDEC1 expression is restricted to the macrophage/dendritic cell populations of the gastrointestinal tract and secondary lymphoid tissue. The biological function of ADAMDEC1 is unknown but it has been hypothesised to play a role in immunity. The identification of reduced ADAMDEC1 expression in Crohn’s disease patients has provided evidence of a potential role in bowel inflammation.Methods:Adamdec1-/- mice were exposed to dextran sodium sulphate or infected orally with Citrobacter rodentium or Salmonella typhimurium. The clinical response was monitored.Results:The loss of Adamdec1 rendered mice more susceptible to the induction of bacterial and chemical induced colitis, as evidenced by increased neutrophil infiltration, greater IL-6 and IL-1β secretion, more weight loss and increased mortality. In the absence of Adamdec1, greater numbers of Citrobacter rodentium were found in the spleen, suggestive of a breakdown in mucosal immunity which resulted in bacteraemia.Conclusion:In summary, ADAMDEC1 protects the bowel from chemical and bacterial insults, failure of which may predispose to Crohn’s disease.

Article first published online 28 August 2014.Supplemental Digital Content is Available in the Text.