Escherichia coliPrevents Phagocytosis-Induced Death of Macrophages via Classical NF-κB Signaling, a Link to T-Cell Activation

Abstract

NF-B is a crucial mediator of macrophage inflammatory responses, but its role in the context of pathogeninduced adaptive immune responses has yet to be elucidated. Here, we demonstrate that classical NF-B activation delays phagocytosis-induced cell death (PICD) in Raw 264.7 and bone marrow-derived macrophages (BMDMs) upon ingestion of bacteria from the Escherichia coli laboratory strain Top10. By expression of a nondegradable form of IB␣ (superrepressor) and pyrrolidine dithiocarbamate treatment, prolonged activation of NF-B upon bacterial coculture is suppressed, whereas initial induction is only partially inhibited. This activation pattern results in partial inhibition of cellular activation and reduced expression of costimulatory CD86. Notably, suppression of classical NF-B activation does not influence bacterial uptake rates but is followed by increased production of oxygen radicals and enhanced intracellular killing in Raw macrophages. This is associated with reduced expression of NF-B-dependent antiapoptotic c-IAP-2 and a loss of the mitochondrial transmembrane potential. Accordingly, NF-B inhibition in Raw cells and BMDMs causes increased apoptotic rates within 12 h of bacterial ingestion. Interestingly, accelerated eradication of E. coli in NF-B-inhibited macrophages is associated with reduced antigen-specific T-cell activation in macrophagelymphocyte cocultures. These data suggest that E. coli inhibits PICD of macrophages via classical, antiapoptotic NF-B activation and thus facilitates signaling to T cells. Subsequently, a proper adaptive immune response is likely to be generated. Conclusively, therapeutic inhibition of classical NF-B activation in macrophages may hamper the initiation of adaptive immunity.

CD4+CD25+Foxp3+regulatory T cells induce alternative activation of human monocytes/macrophages

“…Moreover, IL-10-induced suppression of NF-B activation is also found in tumor-associated macrophages, which have an alternatively activated phenotype (33). Furthermore, blocking NF-B activation in classically activated macrophages results in a decreased proinflammatory response and reduced expression of costimulatory markers, whereas the phagocytic capacity remains intact and bacterial killing is enhanced (34). The latter indicates that suppressed NF-B activation does not affect the phagocytic capacity of monocytes/macrophages, which is supported by our data.…”

Oxidized Low-density Lipoprotein-induced Proinflammatory Cytokine Response in Macrophages are Suppressed by CD4⁺CD25⁺Foxp3⁺ Regulatory T Cells Through Downregulating Toll Like Receptor 2-mediated Activation of NF-ĸB

“…Moreover, IL-10-induced suppression of NF-κB activation is also found in tumor-associated macrophages, which have an alternatively activated phenotype [26]. Furthermore, blocking NF-κB activation in classically activated macrophages results in a decreased proinflammatory response and reduced expression of costimulatory markers, whereas the phagocytic capacity remains intact and bacterial killing is enhanced [18]. More recent reports have shown NF-κB has tissue-specific roles in inflammation; although NF-κB activation in epithelial cells is required to drive the inflammatory response, NF-κB activity in macrophages has an opposing role in the resolution of inflammation.…”

“…NF-κB is a ubiquitous transcription factor that regulates expression of proinflammatory and antiapoptotic genes and is thought to play an important role in driving the inflammatory response [18]. Therefore, we examined NF-κB activity in macrophages cocultured with or without Fig.…”

Neisseria gonorrhoeae Infection Protects Human Endocervical Epithelial Cells from Apoptosis via Expression of Host Antiapoptotic Proteins

“…The extent of protection induced by purified PIB appeared lower than that observed with whole live bacteria, but the amount of porin used was approximately equivalent to the amount of porin which would be found in a culture of live bacteria (MOI, 100). This suggests that PIB (8,26,40,55,56). We thus measured NF-B nuclear translocation in End/E6E7 cells following stimulation with N. gonorrhoeae.…”