Autocrine Type I Interferon Amplifies Dendritic Cell Responses to Lipopolysaccharide via the Nuclear Factor‐κB/p38 Pathways

Abstract

The central role of dendritic cells (DC) in the initiation of immune responses requires these cells to be able to determine the degree of danger in their microenvironment. Abrogating the activity of type I interferon (IFN) secreted after lipopolysaccharide (LPS) stimulation of DC inhibits CD86 and human leucocyte antigen-DR (HLA-DR) upregulation at a low LPS concentration. At a higher concentration of LPS, while changes in surface phenotype are not dependent on type I IFN, this cytokine is required for maximal secretion of interleukin-12 (IL-12) and tumour necrosis factor-a (TNFa) by DC. Thus, the secretion and autocrine activity of type I IFN after Toll-like receptor stimulation enables DC to orchestrate a hierarchical maturation response with regard to changes in surface phenotype and secretion of cytokines. In addition, the activation of nuclear factor-kB and p38 pathways in DC can occur either in an additive fashion when DC are exposed to dual stimulation or can be activated in discrete phases over time when DC are exposed to LPS alone. The differential activation of these pathways provides a mechanism for DC to integrate the activation by multiple stimuli and thus amplify responses to pathogen infection.

Aldose Reductase Mediates the Lipopolysaccharide-induced Release of Inflammatory Mediators in RAW264.7 Murine Macrophages

“…LPS, an endotoxin found in the outer membrane of Gram-negative bacteria, is a major trigger of septic shock (1-3), which is, in part, a consequence of the hosts response to overwhelming bacterial infection. Sepsis is characterized by microvascular thrombosis, decreased organ perfusion, and organ ischemia, which leads to multiorgan dysfunction and death (2,5,26). Innate immune cells such as macrophages recognize the presence of invading bacteria and initiate the host response by releasing cytokines and chemokines (6).…”

“…When Gram-negative bacteria multiply in the host, LPS is released into the circulation, where it is recognized by a variety of circulating cell types, triggering the induction of NF-B-dependent proinflammatory cytokines such as tumor necrosis factor-␣ (TNF-␣), interleukin (IL)-1, prostaglandins, and nitric oxide (1)(2)(3). Acting in an autocrine and paracrine manner, cytokines and chemokines induce and amplify the host response to bacterial infection (4,5). However, excessive cytokine release can have deleterious consequences.…”

Zinc Induces Dendritic Cell Tolerogenic Phenotype and Skews Regulatory T Cell–Th17 Balance

“…For example, transient plasma Zn deficiency in sepsis aggravates inflammatory cytokine production and mortality, while Zn supplementation partially restores protection (38, 39). The cytokines produced by DCs initiate autocrine feedback mechanisms that maintain DC activation (40). Our finding that Zn modulates the proinflammatory response and phenotype of DCs upon fungal infection or TLR challenge, suggests that manipulation of the cytokine environment by this metal may impact autocrine feedback mechanisms leading to control of the DC activation state.…”

Blockade of exosome generation with GW4869 dampens the sepsis-induced inflammation and cardiac dysfunction

“…Additionally, rat cardiomyocytes incubated with LPS-treated macrophages exhibited a significant reduction in contractility, suggesting a direct cross-talk between macrophages and cardiomyocytes [24]. Several studies have also implicated macrophages as autocrine and paracrine signaling mediators that initiate further inflammatory responses in both neighboring macrophages and other types of cells [25, 26]. Recently, exosomes isolated from mycobacterium-treated macrophages were found to be pro-inflammatory in naive macrophages [27, 28].…”