Review: Molecular mechanisms of endotoxin tolerance

Abstract

The phenomenon of endotoxin tolerance has been widely investigated, but to date, the molecular mechanisms of endotoxin tolerance remain to be resolved clearly. The discovery of the Toll-like receptor (TLR) family as the major receptors for lipopolysaccharide (LPS) and other bacterial products has prompted a resurgence of interest in endotoxin tolerance mechanisms. Changes of cell surface molecules, signaling proteins, pro-inflammatory and anti-inflammatory cytokines and other mediators have been examined. During tolerance expression of LPS-binding protein (LBP), CD14, myeloid differentiation protein-2 (MD-2) and TLR2 are unchanged or up-regulated, whereas TLR4 is transiently suppressed or unchanged. Proximal post-receptor signaling proteins that are altered in tolerance include augmented degradation of interleukin-1 receptor-associated kinase (IRAK), and decreased TLR4-myeloid differentiation factor 88 (MyD88) and IRAK-MyD88 association. Tolerance has also been shown to be associated with decreased G i protein content and activity, decreased protein kinase C (PKC) activity, reduction in mitogen-activated protein kinase (MAP kinase) activity, and reduced activator protein-1 (AP-1) and nuclear factor kappa B (NF-kB) induced gene transactivation. However, not all signaling proteins and pathways are suppressed in tolerance and induction of specific anti-inflammatory proteins and signaling pathways may serve important counter inflammatory functions. The latter include induction of IRAK-M and suppressor of cytokine-signaling-1 (SOCS-1), phosphoinositide-3-kinase (PI3K) signaling, and increased or maintained expression of inhibitor-kB (IkB) isoforms. Also at the nuclear level, increase in the NF-kB subunit p50 homodimer expression and increased activation of peroxisome-proliferatoractivated receptors-g (PPARg) have been linked to tolerance phenotype. Although there are species and cellular variations in manifestation of the LPS tolerant phenotype, it is clear that the tolerance phenomena have evolved as a complex orchestrated counter regulatory response to inflammation.

Modulation of splenic immune responses to bacterial lipopolysaccharide in rainbow trout (Oncorhynchus mykiss) fed lentinan, a beta-glucan from mushroom Lentinula edodes

“…Sensing of LPS is initiated by binding to circulatory LBP [55] and in this respect it is noteworthy to mention that expression of BPI/ LBP was more strongly down-regulated in L than in C. A complex of LBP and CD14 activates TLR4 [56], which is believed to play a pivotal role in LPS signaling in mammals. The marked differences in the LPS sensing between salmonid fishes and mammals can be due to the absence and/or functional differences of TLR4, which has not been identified to date [57] and accessory molecules including MD2, CD14, TRAM/TICAM2 and LBP.…”

Innate Memory Reprogramming by Gold Nanoparticles Depends on the Microbial Agents That Induce Memory

“…The first type of innate memory described in mammals is known as "endotoxin tolerance" and results in a less potent secondary response to gram-negative endotoxin or other bacterial challenges, aiming at attaining sufficient protection while avoiding the substantial damage to the host tissues and organs that can be caused by a full innate/inflammatory response, which includes the deadly endotoxin shock (8)(9)(10)(11). In other cases, e.g., in the case of exposure to the tuberculosis vaccine BCG or to the fungal b-glucan, the memory response results in a potentiated reaction ("trained immunity") (6,12).…”

“…This would contribute on one side to the implementation of a more thorough safety evaluation of AuNPs and, on the other hand, it could open the way to a targeted use of this nanomaterial for the therapeutic modulation of innate immunity/inflammation in several immune-related and inflammatory diseases. In particular, this study has addressed innate memory, i.e., the ability of monocytes/macrophages to activate a more protective reaction to a challenge when previously exposed to the same or a different infectious agent(6,7,(9)(10)(11)(12)(13)(14)(15)(16)(17). Following previous studies showing that endotoxin-free Au and other NPs are essentially unable to induce innate/inflammatory responses and innate memory per se, but could at least in part modulate the memory induced by microbial agents(21)(22)(23)(24)(25)(26)72), here we have examined if the nature of the memory-inducing microbial agents could determine the capacity of AuNPs to interfere with the development of innate memory.…”

Inhibition of indoleamine 2,3‐dioxygenase attenuates endotoxin‐mediated tolerance in granulosa cells through kynurenine pathway

“…5 It is well known that innate immune cells during various types of infection undergo protective adaptations and one of such adaptive mechanisms is ET, in which cells enter into a transient unresponsive state and are unable to respond to further challenges with endotoxin. [7][8][9] Since GCs behave like immune cells and, therefore, we hypothesized that GCs can also undergo tolerance. Accordingly, we have mimicked the ET by repeated exposure of endotoxin to GCs till the GCs become unable to respond endotoxin in vitro.…”

“…6 One such adaptive mechanisms is endotoxin tolerance (ET), in which cells enter into a temporary insensitive state and are unable to respond to further challenges with endotoxin. [7][8][9] Many studies in immune cells have shown that the repeated exposure with endotoxin leads to the reduced ability of cells to secrete proinflammatory cytokines. 10 Similarly, we hypothesized that the TLRexpressing GCs can induce immunity as well as undergo tolerance.…”