Abstract
Hyperglycaemia provides a suitable environment for infections and the mechanisms of glucose toxicity include the formation of advanced glycation end-products (AGEs), which comprise non-enzymatically glycosylated proteins, lipids, and nucleic acid amino groups. Among AGE-associated phenotypes, glycolaldehyde-derived toxic AGE (AGE-3) is involved in the pathogenesis of diabetic complications. Internalisation of endotoxin by various cell types contributes to innate immune responses against bacterial infection. An endotoxin derived from Gram-negative bacteria, lipopolysaccharide (LPS), was reported to enhance its own uptake by RAW264.7 mouse macrophage-like cells, and an LPS binding protein, CD14, was involved in the LPS uptake. The LPS uptake induced the activation of RAW264.7 leading to the production of chemokine CXC motif ligand (CXCL) 10, which promotes T helper cell type 1 responses. Previously, we reported that AGE-3 was internalised into RAW264.7 cells through scavenger receptor-1 Class A. We hypothesized that AGEs uptake interrupt LPS uptake and impair innate immune response to LPS in RAW264.7 cells. In the present study, we found that AGE-3 attenuated CD14 expression, LPS uptake, and CXCL10 production, which was concentration-dependent, whereas LPS did not affect AGE uptake. AGEs were reported to stimulate the receptor for AGEs and Toll-like receptor 4, which cause inflammatory reactions. We found that inhibitors for RAGE, but not Toll-like receptor 4, restored the AGE-induced suppression of CD14 expression, LPS uptake, and CXCL10 production. These results indicate that the receptor for the AGE-initiated pathway partially impairs the immune response in diabetes patients.
Highlights
We investigated the effect of advanced glycation end-products (AGEs) on the responses of RAW264.7 cells to LPS
On the basis of accumulating evidence that chronic inflammation, characterised as systemic low-grade inflammation induced by the activation of innate immune cells, provides a basis for understanding the pathophysiology of diabetes mellitus [34] and induces immunosuppression after infection [35, 36], we examined the regulation of macrophage activation
We reported that a toxic AGE, AGE-3, at 200 or 500 μg/mL enhanced the activation of RAW264.7 macrophage-like cells after 4 or 1 h treatment by stimulating scavenger receptor-1 class A (SR-A) or TLR2/4, respectively, but not receptor for AGE (RAGE) [15, 37]
Summary
Lipopolysaccharide (LPS), a potent macrophage activator, activates two signalling pathways, the Toll-like receptor 4 (TLR4)/myeloid differentiation primary response 88 (MyD88)/nuclear factor kappa B (NF-κB) pathway and the TLR4/TIR domain containing adaptor inducing. The dimerised TLR4/MD-2 complex that binds to LPS is internalised and forms an endosome mediated by CD14 This complex on the endosomal membrane activates TRIF-dependent signalling and facilitates the transcription of interferon (IFN) and IFN-inducible genes, such as CXC chemokine ligand 10 (CXCL10/ IFN inducible protein 10, IP10), mediated by the phosphorylation of IRF3. Taken together, these results indicate that CD14 plays important roles in the LPS-initiated signalling pathway for inflammatory responses of macrophages. Because CXCL10 promotes Th1 responses [38], the suppression of CXCL10 production might be a mechanism to evade host immunity These findings suggest that the blockade of AGE-RAGE signalling normalises innate immune responses by macrophages in a diabetes environment
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