Molecular Mechanisms That Underlie the Dynamic Adaptation of Innate Monocyte Memory to Varying Stimulant Strength of TLR Ligands

Abstract

In adaptation to rising stimulant strength, innate monocytes can be dynamically programed to preferentially express either pro- or anti-inflammatory mediators. Such dynamic innate adaptation or programing may bear profound relevance in host health and disease. However, molecular mechanisms that govern innate adaptation to varying strength of stimulants are not well understood. Using lipopolysaccharide (LPS), the model stimulant of toll-like-receptor 4 (TLR4), we reported that the expressions of pro-inflammatory mediators are preferentially sustained in monocytes adapted by lower doses of LPS, and suppressed/tolerized in monocytes adapted by higher doses of LPS. Mechanistically, monocytes adapted by super-low dose LPS exhibited higher levels of transcription factor, interferon regulatory factor 5 (IRF5), and reduced levels of transcriptional modulator B lymphocyte-induced maturation protein-1 (Blimp-1). Intriguingly, the inflammatory monocyte adaptation by super-low dose LPS is dependent upon TRAM/TRIF but not MyD88. Similar to LPS, we also observed biphasic inflammatory adaptation and tolerance in monocytes challenged with varying dosages of TLR7 agonist. In sharp contrast, rising doses of TLR3 agonist preferentially caused inflammatory adaptation without inducing tolerance. At the molecular level, the differential regulation of IRF5 and Blimp-1 coincides with unique monocyte adaptation dynamics by TLR4/7 and TLR3 agonists. Our study provides novel clue toward the understanding of monocyte adaptation and memory toward distinct TLR ligands.

Leukocyte transcriptional signatures dependent on LPS dosage in human endotoxemia

“…The magnitude of the immune response is dependent on the strength of the external stimulus. LPS (endotoxin) is part of the outer membrane of Gram‐negative bacteria and a potent activator of immune cells . LPS induces a robust inflammatory response after its recognition by the myeloid differentiation protein (MD)2, TLR4, and cluster of differentiation (CD)14 macromolecular complex .…”

Programming and memory dynamics of innate leukocytes during tissue homeostasis and inflammation

“…We recently reported that defective completion of the autophagy process via disruption of autolysosome fusion may skew innate monocytes into a nonresolving inflammatory state with elevated expression of selective inflammatory mediators [7]. Disrupted autolysosome fusion may cause an accumulation of inflamed autophagosomes triggering activation of the transcription factor IRF5 [7,15]. We also identified Tollip as a key mediator in the proper formation of the autolysosome [48].…”

“…These negative regulators may attenuate cellular signaling, as well as epigenetically remodel and suppress selected chromatin associated with the expression of proinflammatory mediators [13,14]. In addition to endotoxin, TLR7 and TLR9 agonists may similarly induce monocyte tolerance with similar molecular mechanisms [15,16].…”

“…To achieve selective priming and tolerance of monocytes, the signaling adaptor molecules MyD88 and TRIF may be differentially used [15]. MyD88-dependent signaling was shown to be responsible for the induction of negative-feedback regulators required for tolerance adaptation [25].…”

“…MyD88-dependent signaling was shown to be responsible for the induction of negative-feedback regulators required for tolerance adaptation [25]. In contrast, the adaptors TRAM/TRIF may be selectively involved in the establishment of a nonresolving inflammatory state through the disruption of negative modulators [15]. At the functional level, TRAM/TRIF deficiency has been associated with reduced chronic inflammation in an animal model of atherosclerosis [26].…”