Local and remote tissue injury upon intestinal ischemia and reperfusion depends on the TLR/MyD88 signaling pathway

Abstract

Innate immune responses against microorganisms may be mediated by Toll-like receptors (TLRs). Intestinal ischemia-reperfusion (i-I/R) leads to the translocation of bacteria and/or bacterial products such as endotoxin, which activate TLRs leading to acute intestinal and lung injury and inflammation observed upon gut trauma. Here, we investigated the role of TLR activation by using mice deficient for the common TLR adaptor protein myeloid differentiation factor 88 (MyD88) on local and remote inflammation following intestinal ischemia. Balb/c and MyD88(-/-) mice were subjected to occlusion of the superior mesenteric artery (45 min) followed by intestinal reperfusion (4 h). Acute neutrophil recruitment into the intestinal wall and the lung was significantly diminished in MyD88(-/-) after i-I/R, which was confirmed microscopically. Diminished neutrophil recruitment was accompanied with reduced concentration of TNF-alpha and IL-1beta level. Furthermore, diminished microvascular leak and bacteremia were associated with enhanced survival of MyD88(-/-) mice. However, neither TNF-alpha nor IL-1beta neutralization prevented neutrophil recruitment into the lung but attenuated intestinal inflammation upon i-I/R. In conclusion, our data demonstrate that disruption of the TLR/MyD88 pathway in mice attenuates acute intestinal and lung injury, inflammation, and endothelial damage allowing enhanced survival.

Oxidative Stress: An Essential Factor in the Pathogenesis of Gastrointestinal Mucosal Diseases

“…I/R activates Toll-like receptors (TLRs) leading to acute intestinal and lung injury and inflammation observed during gut trauma (303). The tissue damage due to reperfusion is primarily caused by reentry of oxygen, rather than by ischemia itself.…”

Triggering receptor expressed on myeloid cells -1 as a new therapeutic target during inflammatory diseases

“…50 While ischemia induced little damages by itself, reperfusion leads to a systemic release of several proinflammatory cytokines (TNFα, IL-1β and IL-6) in parallel of leukocyte activation and bacterial translocation, believed to play a crucial role in the induction of local and remote organ failure. Recent evidences show that those phenomena are dependant or TLR/MyD88 signaling pathway 51 and that a NFκB inhibitor prevents organ injury. 52 As TREM-1 as systemic spreading of bacteria.…”

Bacterial Translocation from Intestine: Microbiological, Immunological and Pathophysiological Aspects

“…Последующее развитие воспаления связано с каскадом био-и цитохимических реакций, участием цитокинов и других факторов воспа-ления, таких как цитозольный адаптерный белок MyD88, каспазы, инфламмасомы. Патогенетическая значимость MyD88 подтверждена тем, что у мышей, дефицитных по этому фактору, при ишемических/реперфузионных нарушениях в кишечнике или легких снижались прояв-ления воспаления, что также связывалось с торможением выработки фактора некроза опухоли и интерлейкина 1β, при этом выживаемость животных повышалась [47]. Сигнальные процессы, реализуемые через клеточно-спе-цифическую молекулу MyD88, одновременно приводят к индукции, хемотаксису и накоплению нейтрофилов, что указывает на центральную роль этого сигнального белка, а также на возможность его использования в качестве те-рапевтической мишени [48].…”