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.
Highlights
Emerging studies suggest that innate leukocytes may adopt “rudimentary” memory states depending on challenge history and strength, as reflected in the priming and tolerance paradigm of monocytes challenged with varying dosages of bacterial endotoxin lipopolysaccharide (LPS) [1]
Monocytes challenged with super-low dose LPS (100 pg/ml) were adapted to express significantly higher levels of inflammatory mediators (IL-12 and CCR5) as compared to either non-adapted monocytes or high dose LPS-adapted monocytes (Figures 1A,B; Figure S3 in Supplementary Material)
To determine the molecular mechanisms responsible for the dynamic adaptation of monocytes, we examined the cellular levels of interferon regulatory factor 5 (IRF5) and B lymphocyte-induced maturation protein-1 (Blimp-1)
Summary
Emerging studies suggest that innate leukocytes may adopt “rudimentary” memory states depending on challenge history and strength, as reflected in the priming and tolerance paradigm of monocytes challenged with varying dosages of bacterial endotoxin lipopolysaccharide (LPS) [1]. Dynamic Adaptation of Innate Monocyte Programing cytokine storm followed by suppression of inflammation and tolerance [2]. Both the dramatic upswing of inflammatory cytokines as well as the late-phase refractory tolerance contribute to severe morbidity and mortality associated with sepsis [3]. Subclinical leakage of super-low dose LPS may occur in humans with chronic low-grade inflammatory disease [4, 5]. Monocytes with prolonged adaptation to super-low dose LPS fail to develop tolerance and give rise to a non-resolving low-grade inflammatory phenotype conducive for chronic inflammatory disease [6]. Differential monocyte adaptations to challenges by other microbial products have not been well studied
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