Mechanisms of sterile inflammation and modulation of TLR4 activity

Toll- like receptor (TLR) 4 mediates septic and sterile inflammation. To inhibit TLR4-mediated pro-inflammatory signaling and the resultant pathologies, we analyzed synthetic tetraacylated antagonists. Effective inhibition of the LPS-induced pro-inflammatory activity of human PBMCs was achieved by the long-chain LPS mimetics DA193, DA253, and DA256. In contrast, in mouse BMMs DA-compounds possessing shorter ß-hydroxy- fatty acids, namely DA256, DA255, and DA254 exhibited the most pronounced antagonistic effect. These mimetics were TLR4 specific as they did not impair Cl075 (TLR7/8) driven cell activation. Synthetic agonists induced cytokine (IL-6) and chemokine (CXCL1/KC) production in a TLR4-dependent manner. TLR4 antagonists and agonists are promising candidates for development of therapeutically applicable anti-inflammatory and adjuvant compounds. Furthermore, human TLR8 not only replaces TLR13 but in addition senses mitochondrial rRNA and 16S rRNA derived oligo deoxyribonucleotide (BtmtD3_4) in a UR/R motif dependent manner. Responsiveness of Tlr8-/-- and Unc93b1-/- THP-1 cells towards mitochondrial RNA was abrogated. TLR8 gain of function experiments further indicated 16S mitochondrial rRNA derived ORN (BtmtD3_4) as TLR8-specific. Blocking TLR8 at the early phase of bacterial sepsis besides antibiotic therapy is thus a promising strategy. Severe trauma through tissue damage triggers an inflammatory response which correlates with severity of injury and is associated to mortality and morbidity as in sepsis. Exposed to ionizing radiation as a surrogate trigger of sterile tissue damage, Myd88-/- and Irak4-/- mice quickly succumbed to irradiation sickness pathology. Systemic immune response of comprehensively TLR activity deficient 3d/Tlr2/4/5-/- and germ-free axenic mice exposed to ionizing radiation was unremarkable, whereas Myd88-/-, Irak4-/-, and Il1α/ß-/- mice were insensitive. Accordingly, radiation insult of primed murine BMMs not only induced necroptosis, but also a substantial extracellular accumulation of IL-1ß. Our results implicate release of unprocessed IL-1ß rather than PRR activation as a major source of ionizing irradiation driven sterile inflammation. Whether DNA damage response proteins and caspases are involved needs to be analyzed. Ischemia/reperfusion injury elicits inflammatory responses in the absence of a microbial component, yet poses a potentially lethal threat to the host and solid organ allograft, also with profound influence on acute as well as long-term graft function. In an in vitro model mimicking the organ storage phase prior to transplantation, necrotized cell homogenates induced inflammatory mediator production in a TLR4 and endosomal TLR dependent manner.


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