Detoxifying endotoxin: time, place and person

Abstract

Animals that cannot sense endotoxin may die if they are infected by Gram-negative bacteria. Animals that sense endotoxin and respond too vigorously may also die, victims of their own inflammatory reactions. The outcome of Gram-negative bacterial infection is thus determined not only by an individual's ability to sense endotoxin and respond to its presence, but also by numerous phenomena that inactivate endotoxin and/or prevent harmful reactions to it. Endotoxin sensing requires the MD-2/TLR4 recognition complex and occurs principally in local tissues and the liver. This review highlights the known detoxification mechanisms, which include: (i) proteins that facilitate LPS sequestration by plasma lipoproteins, prevent interactions between the bioactive lipid A moiety and MD-2/TLR4, or promote cellular uptake via non-signaling pathway(s); (ii) enzymes that deacylate or dephosphorylate lipid A; (iii) mechanisms that remove LPS and Gram-negative bacteria from the bloodstream; and (iv) neuroendocrine adaptations that modulate LPS-induced mediator production or neutralize pro-inflammatory molecules in the circulation. In general, the mechanisms for sensing and detoxifying endotoxin seem to be compartmentalized (local versus systemic), dynamic, and variable between individuals. They may have evolved to confine infection and inflammation to extravascular sites of infection while preventing harmful systemic reactions. Integration of endotoxin sensing and detoxification is essential for successful host defense.

C3H/HeJ mice carrying a toll-like receptor 4 mutation are protected against the development of insulin resistance in white adipose tissue in response to a high-fat diet

“…They also highlight the contribution of the TLR4 pathway to the control of obesity and its related complications. We propose that interventions known to reduce endotoxin toxicity [51] or to modulate the TLR4 pathway may help control some key elements of the metabolic syndrome.…”

The bactericidal/permeability-increasing protein (BPI) in infection and inflammatory disease

“…In contrast to many of the clinical trials in which rBPI 21 was continuously infused to maintain functionally significant plasma levels and the target was systemic endotoxin and/or GNB [14,15,64], early interactions of BPI with GNB and endotoxin during natural infections are much more likely to occur in tissue, outside of the bloodstream [3]. Typically, the critical initial event in invasive GNB infections is the crossing of epithelial barriers by the microorganism, particularly those of the skin, lungs, the gastrointestinal and urogenital tracts, and the subsequent exposure of underlying host tissue to the microbe and its products ( Figure 3, [3]).…”

“…Acyloxyacyl hydrolase converts hexa-acylated endotoxins that are potent TLR4 agonists to tetra-acylated species that are TLR4 antagonists [3,105,106]. Endotoxin associated with intact bacteria and bacterial remnants is also partially deacylated in the extracellular inflammatory fluid [88] but at a much slower rate.…”

“…Typically, the critical initial event in invasive GNB infections is the crossing of epithelial barriers by the microorganism, particularly those of the skin, lungs, the gastrointestinal and urogenital tracts, and the subsequent exposure of underlying host tissue to the microbe and its products ( Figure 3, [3]). The outcome of an infection with GNB strongly depends on the host's ability to sense the bacteria in tissue and, if necessary, mount a timely and sufficient inflammatory response that is resolved after the bacteria have been killed and their remnants eliminated [3,65]. Sensitive and potent acute inflammatory responses followed by efficient elimination of viable bacteria and bioactive products help contain the infection and inflammation within tissue and return these sites to resting conditions after resolution of infection-induced inflammation.…”

“…Endotoxins consist of a highly conserved lipid A region, a core polysaccharide region and, in the case of many LPS species, a repeating tetraor penta-saccharide that constitutes the O-antigen ( Figure 1C). Endotoxins can induce potent responses in a wide range of host species including humans by rapidly inducing cellular biosynthesis and release of pro-inflammatory cytokines like tumor necrosis factor α (TNF α) and other bioactive metabolites and by rapidly activating extracellular complement, clotting, and fibrinolytic pathways [3]. Host responses to endotoxin in tissue generally promote protective inflammatory host-defense responses but similar responses systemically can lead to pathological responses ranging from fever and chills to the fulminant sepsis syndrome with multi-organ failure and high mortality [4].…”