Induction of endotoxin tolerance in vivo inhibits activation of IRAK4 and increases negative regulators IRAK-M, SHIP-1, and A20

Abstract

TLRs mediate host defense against microbial pathogens by eliciting production of inflammatory mediators and activating expression of MHC, adhesion, and costimulatory molecules. Endotoxin tolerance limits excessive TLR-driven inflammation during sepsis and reprograms macrophage responses to LPS, decreasing expression of proinflammatory cytokines without inhibiting anti-inflammatory and antimicrobial mediators. Molecular mechanisms of reprogramming of TLR4 signaling upon in vivo induction of endotoxin tolerance are incompletely understood. We used an in vivo model of endotoxin tolerance, whereby C57BL/6 mice were i.p.-inoculated with LPS or PBS, followed by in vitro challenge of peritoneal or splenic macrophages with LPS to examine activation of IRAK4 and expression of negative regulatory molecules. Administration of LPS in vivo-induced endotoxin tolerance in peritoneal and splenic macrophages, as evidenced by decreased degradation of IκBα, suppressed phosphorylation of p38 and reduced expression of TNF-α, IL-6, and KC mRNA upon in vitro LPS challenge. Macrophages from control and endotoxin-tolerant mice exhibited comparable TLR4 mRNA levels and similar expression of IL-1RA and IL-10 genes. Endotoxin tolerization in vivo blocked TLR4-driven IRAK4 phosphorylation and activation in macrophages, while increasing expression of IRAK-M, SHIP-1, A20 mRNA, and A20 protein. Thus, induction of endotoxin tolerance in vivo inhibits expression of proinflammatory mediators via impaired activation of IRAK4, p38, and NF-κB and increases expression of negative regulators of TLR4 pathways.

Mesenchymal stem cells promote macrophage polarization toward M2b-like cells

“…The second LPS stimulation can inhibit TNF expression [41]. It is also apparent from our results that the presence of MSCs is permissive for TNF production although in diminished quantities.…”

NFκB2/p100 Is a Key Factor for Endotoxin Tolerance in Human Monocytes: A Demonstration Using Primary Human Monocytes from Patients with Sepsis

“…In-depth studies of ET have analyzed the participation of a number of factors and have established the role of several negative regulators, such as IRAK-M, ST2, suppressor of cytokine signaling 1, short version of MyD88 and SHIP, as well as the dysregulation of TLR4 and TREM-1 (4,12,29,30), roles that have been observed occasionally in different models (1,9). Among them, the pseudokinase IRAK-M is one of the genes that is consistently induced into ET regardless of the model used (13,31).…”

“…Studies using gene-deficient mice have shown that intracellular molecules such as A20, SHIP-1, and IL-1R-associated kinase monocyte (IRAK-M) play important roles in the development of ET (9)(10)(11)(12). However, due to differences between the innate immune systems of humans and rodents, these molecules might not contribute to human ET development.…”

Epigenetic Regulation of Tolerance to Toll-Like Receptor Ligands in Alveolar Epithelial Cells

“…The induction of negative regulators of TLRs is important in mediating endotoxin tolerance in macrophages and intestinal epithelial cells (21)(22)(23)(24). To determine whether negative regulators of TLRs could also promote endotoxin tolerance in AECs, mRNA expression of IRAK-M, Tollinteracting protein (Tollip), and SIGIRR were measured in tolerized AECs.…”