Community Series in The Role of Toll-like Receptors and their Related Signaling Pathways in Viral Infection and Inflammation: Volume II

(A) Log2 expression of two kinases central to the canonical (left) and non-canonical (right) NF-κB pathways. (B) Key components of the canonical and non-canonical NF-κB pathways exhibit different regulatory patterns. Y-axis: Log2 expression. *indicates significant differential expression (adjusted p < 0.05). (C) StringDB protein–protein association network for the proteins encoded by the 70 genes commonly induced during acute responses by the four toll-like receptor ligands. Nodes: proteins. Edges protein–protein association. Colors: yellow: tolerized; red: super-induced; gray: no memory pattern. (D) Western Blot analysis of p105, p50, and BCL3 expression in cells stimulated for 24 h with ligand for TLR4, TLR2, TLR9, and TLR3 as indicated. (E) Characterization of differential expression and memory status of NF-κB target genes. Figure 7E overlap between NF-κB target genes and differentially expressed genes (adjusted p < 0.05, any acute infection). Number of genes per pattern is indicated in each colored circle. Circle overlaps show numbers of genes with both patterns, either due to multiple differently behaving probes, or ligand-specific memory pattern differences.

Original Research

14 May 2018

Toll-Like Receptors Drive Specific Patterns of Tolerance and Training on Restimulation of Macrophages

Suzanne K. Butcher

, 2 more and

Ruaidhrí J. Carmody

Tolerance is a long-recognized property of macrophages that leads to an altered response to repeated or chronic exposure to endotoxin. The physiological role of tolerance is to limit the potential damage to host tissue that may otherwise result from prolonged production of pro-inflammatory cytokines. Tolerance is induced by all toll-like receptor (TLR) ligands tested to date, however, tolerance induced by the TLR4 ligand lipopolysaccharide (LPS) is by far the best studied. LPS tolerance involves a global transcriptional shift from a pro-inflammatory response toward one characterized by the expression of anti-inflammatory and pro-resolution factors. Although largely reversible, LPS-tolerance leads to a hybrid macrophage activation state that is pro-inflammatory in nature, but possesses distinct regulatory anti-inflammatory features. Remarkably, a comparative transcriptomic analysis of tolerance induced by different TLR ligands has not previously been reported. Here, we describe the transcriptomic profiles of mouse macrophages tolerized with ligands for TLR2, TLR3, TLR4 and TLR 9. While we identified TLR-specific transcriptional profiles in macrophages tolerized with each ligand, tolerance induced by TLR4 represented an archetype pattern, such that each gene tolerized by any of the TLRs tested was also found to be tolerized by TLR4. Pro-inflammatory cytokines are not universally suppressed in all tolerant cells, but distinct patterns of cytokine expression distinguished TLR-specific tolerance. Analysis of gene regulatory regions revealed specific DNA sequence motifs associated with distinct states of TLR tolerance, implicating previously identified as well as novel transcriptional regulators of tolerance in macrophages. These data provide a basis for the future exploitation of TLR-specific tolerant states to achieve therapeutic re-programming of the innate immune response.

14,202 views

98 citations

Review

21 May 2024

Alexandros Popotas

, 2 more and

Nicolas Lefèvre

2,700 views

5 citations

Review

30 January 2018

Toll-like Receptors and Inflammatory Bowel Disease

Yue Lu

, 3 more and

Dekai Zhang

Inflammatory bowel disease (IBD) is one relapsing and lifelong disease that affects millions of patients worldwide. Increasing evidence has recently highlighted immune-system dysfunction, especially toll-like receptors (TLRs)-mediated innate immune dysfunction, as central players in the pathogenesis of IBD. TLRs and TLR-activated signaling pathways are involved not only in the pathogenesis but also in the efficacy of treatment of IBD. By understanding these molecular mechanisms, we might develop a strategy for relieving the experience of long-lasting suffering of those patients and improving their quality of life. The purpose of this review article is to summarize the potential mechanisms of TLR signaling pathways in IBD and the novel potential therapeutic strategies against IBD.

23,236 views

278 citations

Glycans N-linked to TLR2, expressed on the surface of antigen-presenting cells, are targeted by carbohydrate recognition domain (CRD) of some lectins. The established interactions are followed by intracellular signaling and production of cytokines. Fully glycosylated TLR2 molecules can be targeted by lectins CRDs (shown at the right side of the figure), besides recognizing pathogen-associated molecular patterns (PAMPs) and synthetic ligands. Either interaction induces activation of NF-κB signaling pathway and production of cytokines. Most constructed TLR2 glycomutants (exhibiting isolated or combined elimination of N-glycans) preserve the capacity to recognize PAMPs, whereas some of the glycomutants become selectively unresponsive to a specific lectin stimulus (shown at the left side of this figure). This approach allows defining which N-glycans are critically required to trigger TLR2 activation by a lectin. In this illustration, the TLR2 N-glycans (numbered 1–4 and linked to Asn116, Asn199, Asn416, and Asn442) are not rigorously localized in the TLR2 backbone. For a more realistic representation of N-glycans position on TLR2, see the article authored by Weber et al. (13).

Perspective

18 December 2017

Targeting and Recognition of Toll-Like Receptors by Plant and Pathogen Lectins

Rafael Ricci-Azevedo

, 1 more and

Nicholas J. Gay

4,133 views

34 citations