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

View Article: PubMed Central - PubMed

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.

No MeSH data available.


Related in: MedlinePlus

Cross talk between immunoreceptor tyrosine-based activation motif (ITAM)-associated receptor signaling and toll-like receptor (TLR) pathways in conventional dendritic cells (cDCs), MΦ, and plasmacytoid DCs (pDCs): an ITAM-centric view. ITAM-mediated activation pathways are shown by green arrows; ITAM-mediated inhibitory pathways are shown by red lines. Positive or negative control of immune responses in macrophages (MΦ) is determined by avidity of ITAM-associated receptors to their ligands. Production of interferons (IFNs)-I is facilitated by interferon-regulatory factor 3 (IRF3) in macrophages, by IRF5 in cDCs, and by IRF7 in pDCs. In cDCs, ITAM-associated receptor signaling can result in the IRF5-mediated production of IFN-β without engagement of TLRs (31). Alternative pathway in cDCs (32) is shown by dotted arrow.
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Figure 5: Cross talk between immunoreceptor tyrosine-based activation motif (ITAM)-associated receptor signaling and toll-like receptor (TLR) pathways in conventional dendritic cells (cDCs), MΦ, and plasmacytoid DCs (pDCs): an ITAM-centric view. ITAM-mediated activation pathways are shown by green arrows; ITAM-mediated inhibitory pathways are shown by red lines. Positive or negative control of immune responses in macrophages (MΦ) is determined by avidity of ITAM-associated receptors to their ligands. Production of interferons (IFNs)-I is facilitated by interferon-regulatory factor 3 (IRF3) in macrophages, by IRF5 in cDCs, and by IRF7 in pDCs. In cDCs, ITAM-associated receptor signaling can result in the IRF5-mediated production of IFN-β without engagement of TLRs (31). Alternative pathway in cDCs (32) is shown by dotted arrow.

Mentions: Fifteen years after the discovery of the inhibitory role of BDCA-2 in IFN-I production in pDCs (17), its molecular mechanism remains elusive. The signal-switch hypothesis had a seminal role in the understanding of cross-regulation of cytokine- and TLR-signaling pathways in macrophages (8, 9, 28, 39, 58). However, further studies showed that the ITAM-signaling pathway may be regulated in a special way in human pDCs (11, 18–20). While the high-avidity engagement of ITAM-associated receptors in macrophages leads to potentiation of TLR signaling, it results in the attenuation of TLR-induced IFN-I production in pDCs (Figure 5; Table 1). Surprisingly, few data are available on the interplay of ITAM-associated receptors and TLRs in cDCs. Cellular context, spatiotemporal differences, and different functions of ITAM-associated receptors could be responsible for the different interplay of ITAM and TLR pathways in pDCs, cDCs, and macrophages.


Cross Talk between Inhibitory Immunoreceptor Tyrosine-Based Activation Motif-Signaling and Toll-Like Receptor Pathways in Macrophages and Dendritic Cells
Cross talk between immunoreceptor tyrosine-based activation motif (ITAM)-associated receptor signaling and toll-like receptor (TLR) pathways in conventional dendritic cells (cDCs), MΦ, and plasmacytoid DCs (pDCs): an ITAM-centric view. ITAM-mediated activation pathways are shown by green arrows; ITAM-mediated inhibitory pathways are shown by red lines. Positive or negative control of immune responses in macrophages (MΦ) is determined by avidity of ITAM-associated receptors to their ligands. Production of interferons (IFNs)-I is facilitated by interferon-regulatory factor 3 (IRF3) in macrophages, by IRF5 in cDCs, and by IRF7 in pDCs. In cDCs, ITAM-associated receptor signaling can result in the IRF5-mediated production of IFN-β without engagement of TLRs (31). Alternative pathway in cDCs (32) is shown by dotted arrow.
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Related In: Results  -  Collection

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Show All Figures
getmorefigures.php?uid=PMC5383719&req=5

Figure 5: Cross talk between immunoreceptor tyrosine-based activation motif (ITAM)-associated receptor signaling and toll-like receptor (TLR) pathways in conventional dendritic cells (cDCs), MΦ, and plasmacytoid DCs (pDCs): an ITAM-centric view. ITAM-mediated activation pathways are shown by green arrows; ITAM-mediated inhibitory pathways are shown by red lines. Positive or negative control of immune responses in macrophages (MΦ) is determined by avidity of ITAM-associated receptors to their ligands. Production of interferons (IFNs)-I is facilitated by interferon-regulatory factor 3 (IRF3) in macrophages, by IRF5 in cDCs, and by IRF7 in pDCs. In cDCs, ITAM-associated receptor signaling can result in the IRF5-mediated production of IFN-β without engagement of TLRs (31). Alternative pathway in cDCs (32) is shown by dotted arrow.
Mentions: Fifteen years after the discovery of the inhibitory role of BDCA-2 in IFN-I production in pDCs (17), its molecular mechanism remains elusive. The signal-switch hypothesis had a seminal role in the understanding of cross-regulation of cytokine- and TLR-signaling pathways in macrophages (8, 9, 28, 39, 58). However, further studies showed that the ITAM-signaling pathway may be regulated in a special way in human pDCs (11, 18–20). While the high-avidity engagement of ITAM-associated receptors in macrophages leads to potentiation of TLR signaling, it results in the attenuation of TLR-induced IFN-I production in pDCs (Figure 5; Table 1). Surprisingly, few data are available on the interplay of ITAM-associated receptors and TLRs in cDCs. Cellular context, spatiotemporal differences, and different functions of ITAM-associated receptors could be responsible for the different interplay of ITAM and TLR pathways in pDCs, cDCs, and macrophages.

View Article: PubMed Central - PubMed

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.

No MeSH data available.


Related in: MedlinePlus