Cross Talk between Inhibitory Immunoreceptor Tyrosine-Based Activation Motif-Signaling and Toll-Like Receptor Pathways in Macrophages and Dendritic Cells

Abstract

The innate immune cells sense microbial infection and self-ligands by pathogen recognition receptors (PRRs), such as toll-like receptors (TLRs) and regulatory receptors (RRs), associated with immunoreceptor tyrosine-based activation motif (ITAM). Rapid activation and concerted action of PRRs signaling and feedback inhibitory mechanisms must be engaged to ensure the host defense functions and to prevent cytotoxicity associated with excessive activation. ITAM-associated RRs can generate stimulatory or, paradoxically, inhibitory signals. The network of ITAM-associated RR, together with TLR-signaling pathways, are responsible for immunogenic or tolerogenic responses of macrophages and dendritic cells to their microenvironment. In macrophages, TLR4 signaling is inhibited by low-avidity ligation of ITAM-associated receptors, while high-avidity ligation of ITAM-associated receptors results in potentiation of TLR4 signaling together with resistance to extracellular cytokine microenvironment signals. In contrast to macrophages, TLR7/9 signaling in plasmacytoid DCs (pDCs) is inhibited by high-avidity ligation of ITAM-associated RR, while low-avidity ligation does not show any effect. Surprisingly, interference of ITAM-associated receptor signaling with TLR pathways has not been reported in conventional dendritic cells. Here, we present an overview of molecular mechanisms acting at the crossroads of TLR and ITAM-signaling pathways and address the question of how the high-avidity engagement of the ITAM-associated receptors in pDCs inhibits TLR7/9 signaling. Cellular context and spatiotemporal engagement of ITAM- and TLR-signaling pathways are responsible for different outcomes of macrophage versus pDC activation. While the cross-regulation of cytokine and TLR signaling, together with antigen presentation, are the principal functions of ITAM-associated RR in macrophages, the major role of these receptors in pDCs seems to be related to inhibition of cytokine production and reestablishment of a tolerogenic state following pDC activation. Pharmacologic targeting of TLR and ITAM signaling could be an attractive new therapeutic approach for treatment of chronic infections, cancer, and autoimmune and inflammatory diseases related to pDCs.

Molecular mechanisms of macrophage Toll-like receptor–Fc receptor synergy

“…Dendritic cells also express TLR and FcR, and it is known that crosstalk occurs in these cells as well. However, the underlying molecular mechanisms and impact of crosstalk on immune function appear to be different (recently reviewed in 32 ). Future studies on the precise underlying molecular mechanisms in both cell types will yield exciting new insights.…”

MiR‐182‐5p inhibited oxidative stress and apoptosis triggered by oxidized low‐density lipoprotein via targeting toll‐like receptor 4

“…A novel role of miR‐210 has been uncovered in AS progression through regulating endothelial apoptosis (Li, Yang, Zhang, & Yang, ). Recently, miR‐182‐5p has demonstrated abnormal (Hirata et al, ; Hirata et al, ; Hirsch, Janovec, Stranska, & Bendriss‐Vermare, ). MiR‐182‐5p is observed to promote human prostate cancer development via targeting FOXF2, RECK and MTSS1 expression (Hirata et al, ).…”

“…In human bladder cancer, miR‐182‐5p can play an oncogenic role and inhibit Smad4 and RECK (Hirata et al, ). It is reported that miR‐182‐5p is highly upregulated in breast cancer samples (Hirsch et al, ). However, few studies are focused on AS progression, which encouraged us to study the function of miR‐182‐5p in the AS in the current study.…”

“…Toll-like receptors (TLRs), constituting the innate immune system, are expressed by different immune cells (Hirsch et al, 2017). They can recognize various microorganisms and lead to the inflammatory response (Shibolet & Podolsky, 2007).…”

Bcl10 synergistically links CEACAM3 and TLR-dependent inflammatory signalling

“…However, the molecular events that allow separation of these two CEACAM3 effector functions remain unknown. Moreover, from a broader perspective, the molecular processes that allow synergy between ITAM‐containing phagocytic receptors and TLRs remain poorly defined (Hirsch, Janovec, Stranska, & Bendriss‐Vermare, ; Underhill, ). Although human neutrophils express CEACAM1, CEACAM6, and other receptors with the potential to mediate bacterial engulfment, CEACAM3 has been shown to act as the principle phagocytic receptor for N. gonorrhoeae (Schmitter et al, ).…”