Disordered macrophage cytokine secretion underlies impaired acute inflammation and bacterial clearance in Crohn's disease
Andrew M. Smith,Farooq Rahman,Bu’Hussain Hayee,Simon J Graham,Daniel Marks,Gavin W. Sewell,Christine D. Palmer,Jonathan I. Wilde,Brian M. J. Foxwell,Israel S. Gloger,Trevor J. Sweeting,Mark Marsh,Ann P. Walker,Stuart Bloom,Anthony W. Segal +14 more
TLDR
It is suggested that in CD macrophages, an abnormal proportion of cytokines are routed to lysosomes and degraded rather than being released through the normal secretory pathway, which indicates accelerated intracellular breakdown.Abstract:
The cause of Crohn's disease (CD) remains poorly understood. Counterintuitively, these patients possess an impaired acute inflammatory response, which could result in delayed clearance of bacteria penetrating the lining of the bowel and predispose to granuloma formation and chronicity. We tested this hypothesis in human subjects by monitoring responses to killed Escherichia coli injected subcutaneously into the forearm. Accumulation of 111In-labeled neutrophils at these sites and clearance of 32P-labeled bacteria from them were markedly impaired in CD. Locally increased blood flow and bacterial clearance were dependent on the numbers of bacteria injected. Secretion of proinflammatory cytokines by CD macrophages was grossly impaired in response to E. coli or specific Toll-like receptor agonists. Despite normal levels and stability of cytokine messenger RNA, intracellular levels of tumor necrosis factor (TNF) were abnormally low in CD macrophages. Coupled with reduced secretion, these findings indicate accelerated intracellular breakdown. Differential transcription profiles identified disease-specific genes, notably including those encoding proteins involved in vesicle trafficking. Intracellular destruction of TNF was decreased by inhibitors of lysosomal function. Together, our findings suggest that in CD macrophages, an abnormal proportion of cytokines are routed to lysosomes and degraded rather than being released through the normal secretory pathway.read more
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Journal ArticleDOI
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TL;DR: It is suggested that the NOD2 gene product confers susceptibility to Crohn's disease by altering the recognition of these components and/or by over-activating NF-kB in monocytes, thus documenting a molecular model for the pathogenic mechanism of Crohn’s disease that can now be further investigated.
Journal ArticleDOI
A frameshift mutation in NOD2 associated with susceptibility to Crohn's disease
Yasunori Ogura,Denise K. Bonen,Naohiro Inohara,Dan L. Nicolae,Felicia F. Chen,Richard Ramos,Heidi M. Britton,Thomas M. Moran,Reda Karaliuskas,Richard H. Duerr,Jean-Paul Achkar,Steven R. Brant,Theodore M. Bayless,Barbara S. Kirschner,Stephen B. Hanauer,Gabriel Núñez,Judy H. Cho +16 more
TL;DR: It is shown that a frameshift mutation caused by a cytosine insertion, 3020insC, which is expected to encode a truncated NOD2 protein, is associated with Crohn's disease, and a link between an innate immune response to bacterial components and development of disease is suggested.
Journal ArticleDOI
Origin and Physiological Roles of Inflammation
TL;DR: This work has shown that tissue stress or malfunction induces an adaptive response that is intermediate between the basal homeostatic state and a classic inflammatory response, which is referred to here as para-inflammation.
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