innate immune cell memory induced by endogenous and exogenous triggers

Innate memory is a key defence mechanism against infection, enhancing protective immunity and limiting unnecessary collateral tissue damage. Inflammation triggered by endogenous stimuli that signal cellular stress or tissue injury, must also be tightly controlled to balance robust response to intrinsic danger whilst avoiding catastrophic autoimmunity. Here, we assess the contribution of innate memory to this balance. The extracellular matrix protein tenascin-C, a damage-associated, toll-like receptor 4 (TLR4) agonist, reprograms monocyte response to subsequent threat, inducing concomitantly suppressed and enhanced responses to rechallenge. Comparative analysis of memory evoked by tenascin-C and the pathogenic TLR4 agonist, LPS, revealed both common and distinct gene expression signatures, effects that were controlled transcriptionally, These data highlight how intrinsic and extrinsic innate re-programming exerts control over dysregulated inflammatory networks driving either infectious or chronic ‘sterile’ inflammatory diseases. Primary human monocytes from healthy individuals were stimulated for 24hours with LPS (100 ng/mL) or the FBG domain from tenascin-C (FBG-C). Cells were then washed, rested for 5 days, and restimulated for 4 hours with LPS, FBG-C or POLY-I:C (TRIGGER) on day 6 (7D Protocol), or cells washed and immediately restimulated for 2 hours with LPS or FBG-C (24H Protocol). After restimulation with the TRIGGER cells were lysed and transcriptomic changes analyzed by bulk RNAseq. 5 independent donors were analysed.