Disruption of macrophage pro‐inflammatory cytokine release in Crohn's disease is associated with reduced optineurin expression in a subset of patients

Abstract

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.

Critical Role of the Disintegrin Metalloprotease ADAM-like Decysin-1 [ADAMDEC1] for Intestinal Immunity and Inflammation

“…27–29 In addition, peripheral blood monocytes cultured under sterile conditions in vitro upregulate ADAMDEC1 expression as they differentiate into macrophages. 8,16 ADAMDEC1 is not expressed in resident macrophages from extra-intestinal tissues. A number of studies and online datasets demonstrate that ADAMDEC1 is not detectable in mature macrophage populations resident in the peritoneum, lung, liver, and adipose tissues and is only moderately expressed in mature splenic macrophages [GSE56711; GDS2982].…”

“…Furthermore, ADAMDEC1 has been reported as under-expressed in MDM and terminal ileal [TI] tissue from patients with quiescent as well as active Crohn’s disease. 7,8 We predicted that loss of ADAMDEC1 may increase the host’s susceptibility to bacterial infection and intestinal inflammation resulting in the development of Crohn’s disease. This theory was substantiated through the use of a number of GI infection and inflammatory models in Adamdec1 -deficient mice.…”

“…2 ADAMDEC1, first identified in 1997, is the sole member of a subsidiary class of the ADAM family. 1 It has been linked to a number of inflammatory diseases including atherosclerosis, 3 pulmonary sarcoidosis, 4 osteoarthritis, 5,6 Crohn’s disease, 7,8 and to gastrointestinal [GI] malignancies–gastric adenocarcinoma 9, 10 and colorectal cancer. 11, 12 The physiological role of ADAMDEC1 remains to be determined.…”

Making sense of the cause of Crohn’s – a new look at an old disease

“…The most commonly under-expressed gene identified was Optineurin, low expression levels of which were found in 10% of CD patients studied 355 . ADAMDEC1 was under-expressed in about 7% of patients.…”

“…Its biological function is unknown but it has been hypothesised to play a role in immunity. Reduced ADAMDEC1 expression in macrophages from a subgroup of CD patients has provided evidence of a potential role in bowel inflammation 355 . Adamdec1 -/- mice were more susceptible to the induction of bacterial and chemical induced colitis and they cleared Citrobacter rodentium less efficiently than wild-type mice after infection 359 .…”