Toll-like receptors 2 and 4: initiators of non-septic inflammation in critical care medicine?

Abstract

Purpose Although the role of Toll-like receptors (TLRs) in bacterial infection and sepsis is well characterized, recent studies have also shown that TLR4 and TLR2 can play an important role in contributing to acute inflammatory processes and organ dysfunction in settings in which LPS or other bacterial products are not present. This review presents not only insights into pathophysiologic mechanisms that contribute to organ dysfunction and outcome in critical illness, but also direct therapeutic approaches to ameliorating such TLR-mediated responses that may potentially be of clinical benefit in critically ill patients. Method Literature review of the role of TLR4 and TLR2 in sterile inflammation relevant to critical care medicine using PubMed search, including original papers in English from 1990 to 2010. Conclusion There is increasing evidence that TLR4 and TLR2 are not only receptors for bacterial products, but also can be activated through other mechanisms relevant to the pathophysiology of critical illnesses. There is evidence that TLR4 and TLR2 are involved in ischemia-reperfusion injury and trauma where Gram-negative or Gram-positive bacteria are not detectible in the circulation or local organ sites, such as the lungs. In these settings TLRs can transduce other proinflammatory signals and thereby contribute to cellular activation leading to acute lung injury and other organ system dysfunction. The consequences of TLR4 and TLR2 activation through reactive oxygen species (ROS), heat shock proteins, and other non-LPS dependent mechanisms may be different from those associated with binding of the membrane component of bacteria to TLR4 or TLR2 and may produce different signatures of gene activation and release of proinflammatory mediators.

Testosterone protects from metabolic syndrome-associated prostate inflammation: an experimental study in rabbit

“…The increased expression of TLR2, TLR4 mRNA -widely distributed not only in immune but also in non-professional antigen presenting cells, such as stromal prostatic cells (Fibbi et al 2010) -suggests the activation of both innate and specific immune responses. Recent studies have shown that TLR2, TLR4 can play an important role in initiating a proinflammatory cascade, even in clinical settings in which microbial ligands are not present (Lorne et al 2010). Indeed, in our model of MetS-associated prostate inflammation, no nitrites and leukocyte esterase were detected in the urine.…”

Intravenous Endotoxin Challenge in Healthy Humans: An Experimental Platform to Investigate and Modulate Systemic Inflammation

“…Inflammation is initiated by the presence of pathogen-associated molecular patterns (PAMPs) or danger-associated molecular patterns (DAMPs) -commonly intracellular components released via tissue damage [3][4][5] . These conserved molecular motifs bind pattern-recognition receptors (PRRs) such as Toll-like receptors (TLRs) found on epithelial cells, endothelial cells and those of the innate immune system, to trigger common downstream intracellular signaling pathways 6 .…”

Adenylyl Cyclase 6 Activation Negatively Regulates TLR4 Signaling through Lipid Raft–Mediated Endocytosis

“…Without proper regulation, these mechanisms inflict serious damage, and even death, on the host. Improper activation of TLR4 contributes to inflammatory diseases such as acute lung injury (44) and autoimmune diseases like rheumatoid arthritis (45). It is no wonder that hosts balance TLR4 effects to ensure both pathogen clearance and host health.…”