Network Topologies and Dynamics Leading to Endotoxin Tolerance and Priming in Innate Immune Cells

The innate immune system, acting as the first line of host defense, senses and adapts to foreign challenges through complex intracellular and intercellular signaling networks. Endotoxin tolerance and priming elicited by macrophages are classic examples of the complex adaptation of innate immune cells. Upon repetitive exposures to different doses of bacterial endotoxin (lipopolysaccharide) or other stimulants, macrophages show either suppressed or augmented inflammatory responses compared to a single exposure to the stimulant. Endotoxin tolerance and priming are critically involved in both immune homeostasis and the pathogenesis of diverse inflammatory diseases. However, the underlying molecular mechanisms are not well understood. By means of a computational search through the parameter space of a coarse-grained three-node network with a two-stage Metropolis sampling approach, we enumerated all the network topologies that can generate priming or tolerance. We discovered three major mechanisms for priming (pathway synergy, suppressor deactivation, activator induction) and one for tolerance (inhibitor persistence). These results not only explain existing experimental observations, but also reveal intriguing test scenarios for future experimental studies to clarify mechanisms of endotoxin priming and tolerance.Comment: 15 pages, 8 figures, submitte

Activation of the lectin pathway by natural IgM in a model of ischemia/reperfusion injury

Reperfusion of ischemic tissues elicits an acute inflammatory response involving serum complement, which is activated by circulating natural IgM specific to self-Ags exposed by ischemia. Recent reports demonstrating a role for the lectin pathway raise a question regarding the initial events in complement activation. To dissect the individual roles of natural IgM and lectin in activation of complement, mice bearing genetic deficiency in early complement, IgM, or mannan-binding lectin were characterized in a mesenteric model of ischemia reperfusion injury. The results reveal that IgM binds initially to ischemic Ag providing a binding site for mannan-binding lectin which subsequently leads to activation of complement and injury

Serum mannose-binding lectin levels and mbl2 gene polymorphisms in different age and gender groups of southern Chinese adults

Mannose-binding lectin (MBL) is an acute-phase serum protein, and its inherited deficiency has been shown to predispose to infections. The developmental profile of serum MBL in preterm infants has been demonstrated previously. To determine the profiles of serum MBL levels and mbl2 polymorphisms over age and genders in an adult population, samples from 689 southern Chinese (age range 16-57 years; 382 males and 307 females) were studied using enzyme-linked immunosorbent assay and high-throughput genotyping of mbl2. Serum MBL levels maintained within a narrow range from age groups of 16-20 years old to 31-40 years old (mean of 2050-2160 μg/l) and declined to a mean of 1466 μg/l in the last age group 41-57 years old. No significant differences were found in the distributions of mbl2 haplotypes (YA, XA and YB) among all these age groups. Between gender groups, no significant imbalance of MBL profile in terms of serum MBL levels and distribution of mbl2 haplotypes was found. Results suggest an important role of circulating MBL in first-line host defence because MBL maintains at fairly constant levels after childhood and no gender influence on the MBL profile.link_to_subscribed_fulltex