Innate immune sensing and its roots: the story of endotoxin

Abstract

How does the host sense pathogens? Our present concepts grew directly from longstanding efforts to understand infectious disease: how microbes harm the host, what molecules are sensed and, ultimately, the nature of the receptors that the host uses. The discovery of the host sensors--the Toll-like receptors--was rooted in chemical, biological and genetic analyses that centred on a bacterial poison, termed endotoxin.

Interleukin‐10 derived from macrophages and/or neutrophils regulates the inflammatory response to LPS but not the response to CpG DNA

“…An important family of pattern recognition receptors are the Toll like receptors (TLRs), which recognize a diverse spectrum of ligands including nucleic acids, lipids and proteins (reviewed in [1], [2]). TLR4 recognizes lipopolysaccharide (LPS) of Gram-negative bacteria and mediates secretion of proinflammatory cytokines, most notably, TNF-α, IL-12 and IFN-γ (reviewed in [3]). Furthermore, TLR4 stimulation induces dendritic cell maturation and B cell proliferation [3].…”

“…TLR4 recognizes lipopolysaccharide (LPS) of Gram-negative bacteria and mediates secretion of proinflammatory cytokines, most notably, TNF-α, IL-12 and IFN-γ (reviewed in [3]). Furthermore, TLR4 stimulation induces dendritic cell maturation and B cell proliferation [3]. TLR9 triggers an inflammatory response upon recognition of unmethylated CpG motifs in bacterial or viral DNA, which are less common in mammalian DNA (reviewed in [4]).…”

“…The most prominent example of TLR-mediated immunopathology is endotoxic shock [3], which results from an overwhelming production of pro-inflammatory mediators, in particular TNF-α, resulting in systemic microvascular damage. IL-10 is an immunoregulatory cytokine, which limits immune responses and minimizes immunopathology (reviewed in [5]).…”

Importance of heterogeneity in Porhyromonas gingivalis lipopolysaccharide lipid A in tissue specific inflammatory signalling

“…Of the LPS macromolecule, lipid A is responsible for the endotoxic activities, and its recognition by host cells leads to differential immuno-inflammatory responses [4,7–9]. From LPS, it is the heterogeneity within the A-LPS which represents the major virulence factors that promote inflammation and bone loss.…”

The zinc finger protein Gfi1 acts upstream of TNF to attenuate endotoxin‐mediated inflammatory responses in the lung

“…The recognition of foreign intruders is mediated by Toll-like receptors (TLR), which are expressed on the surface of macrophages and other resident lung cells [2]. The outer membrane of Gramnegative bacteria for instance is composed of lipopolysaccharides (LPS) that are recognized by TLR4 [3,4]. After LPS stimulation, TLR4 consecutively triggers recruitment of the adapter protein myeloid differentiation factor 88 (MyD88) [5], the IL-1R-associated kinase (IRAK) [6], members of the TNFR-associated factor family of adapter proteins and finally downstream kinases in order to promote the nuclear translocation and activation of the latent transcription factor NF-jB.…”