Disordered macrophage cytokine secretion underlies impaired acute inflammation and bacterial clearance in Crohn's disease

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.

Functional defects in NOD2 signaling in experimental and human Crohn disease

“…Interestingly, this phenotype was shared by all CD patients tested, regardless of their NOD2 genotype, and was markedly distinct from healthy controls. 32 This parallels our findings that macrophages from SAMP mice (which have a wildtype NOD2 genotype) are refractory to MDP-stimulated cytokine production and MDP-enhanced Salmonella clearance and suggests that NOD2 dysfunction in hematopoietic cells plays a critical role in disease pathogenesis. 27 Moreover, because NOD2 is tightly associated to autophagy, 22 it is possible that the contribution of autophagic mechanisms to the intestinal disease of SAMP mice might be also involved.…”

Hygiene and Other Early Childhood Influences on the Subsequent Function of the Immune System

“…Similarly, the recent claim to have discovered that the ‘cause’ of Crohn’s disease is a genetically determined defect in the homing of neutrophils is difficult to reconcile with the fact that 100 years ago the disease barely existed. It is the recent environmental changes that have caused this phenotype to become a risk factor [50] (fig. 3).…”

<b><i>Trichuris suis</i></b> Ova in Inflammatory Bowel Disease

“…The resulting defects of specially the innate immune system [2,3,5] may explain why immune suppression is able to attenuate or even eliminate acute inflammation in IBD but does not lead to long-term normalization. Some of the genetic susceptibility factors indeed lead to a defect of the barrier resulting in translocation of bacterial DNA and may even result in a decreased response to immune suppressive drugs [6].…”