Spatial Organization of Dectin-1 and TLR2 during Synergistic Crosstalk Revealed by Super-resolution Imaging

Li, Miao; Vultorius, Christopher; Bethi, Manisha; Yu, Yan

doi:10.1021/acs.jpcb.2c03557

Cited by 3 publications

References 51 publications

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The Dectin-1 and Dectin-2 clusters: C-type lectin receptors with fundamental roles in immunity

Malamud,

Brown

2024

EMBO Rep

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The ability of myeloid cells to recognize and differentiate endogenous or exogenous ligands rely on the presence of different transmembrane protein receptors. C-type lectin receptors (CLRs), defined by the presence of a conserved structural motif called C-type lectin-like domain (CTLD), are a crucial family of receptors involved in this process, being able to recognize a diverse range of ligands from glycans to proteins or lipids and capable of initiating an immune response. The Dectin-1 and Dectin-2 clusters involve two groups of CLRs, with genes genomically linked within the natural killer cluster of genes in both humans and mice, and all characterized by the presence of a single extracellular CTLD. Fundamental immune cell functions such as antimicrobial effector mechanisms as well as internalization and presentation of antigens are induced and/or regulated through activatory, or inhibitory signalling pathways triggered by these receptors after ligand binding. In this review, we will discuss the most recent concepts regarding expression, ligands, signaling pathways and functions of each member of the Dectin clusters of CLRs, highlighting the importance and diversity of their functions.

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The Dectin-1 and Dectin-2 clusters: C-type lectin receptors with fundamental roles in immunity

Malamud,

Brown

2024

EMBO Rep

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Nanocluster-Mediated Signaling Crosstalk between FcγR and TLR4 in Macrophage Inflammatory Responses

Lee,

2024

Preprint

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Receptor crosstalk, the interaction between different receptors to modulate signaling, is crucial for fine-tuning the inflammatory responses of innate immune cells. Although the synergistic crosstalk between Toll-like receptor (TLR)4 and Fc gamma receptor (FcγR) is well documented, the detailed mechanism underlying this synergy remains unclear. In this study, we addressed this knowledge gap by imaging the molecular organization of TLR4 and FcγR on the macrophage cell surface and correlating it with their synergistic co-activation using ligands functionalized on lipid bilayers. We confirmed that co-activation of TLR4 and FcγR enhances whole-cell pro-inflammatory responses and tyrosine phosphorylation at the receptor level. Super-resolution microscopy revealed that TLR4 and FcγR each form discrete nanoclusters after ligand stimulation, and their synergistic co-activation significantly increases both the size and spatial overlap of these nanoclusters, leading to amplified immune signaling. Contrary to previous assumptions that TLR4 and FcγR form heterodimers during their crosstalk, our results emphasize the critical role of receptor nanocluster interactions in modulating innate immune responses. Additionally, these findings align with similar receptor interaction mechanisms that we previously reported in other receptor pairs, such as Dectin-1/TLR2 and FcγR/TLR2, suggesting that nanocluster interactions may represent a predominant mechanism governing crosstalk between TLRs and ITAM-containing receptors.

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Zymosan-Induced Murine Peritonitis Is Associated with an Increased Sphingolipid Synthesis without Changing the Long to Very Long Chain Ceramide Ratio

Pierron

Guzylack‐Piriou

Tardieu

et al. 2023

IJMS

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Sphingolipids are key molecules in inflammation and defense against pathogens. Their role in dectin-1/TLR2-mediated responses is, however, poorly understood. This study investigated the sphingolipidome in the peritoneal fluid, peritoneal cells, plasma, and spleens of mice after intraperitoneal injection of 0.1 mg zymosan/mouse or PBS as a control. Samples were collected at 2, 4, 8, and 16 h post-injection, using a total of 36 mice. Flow cytometry analysis of peritoneal cells and measurement of IL-6, IL-1β, and TNF-α levels in the peritoneal lavages confirmed zymosan-induced peritonitis. The concentrations of sphingoid bases, dihydroceramides, ceramides, dihydrosphingomyelins, sphingomyelins, monohexosylceramides, and lactosylceramides were increased after zymosan administration, and the effects varied with the time and the matrix measured. The greatest changes occurred in peritoneal cells, followed by peritoneal fluid, at 8 h and 4 h post-injection, respectively. Analysis of the sphingolipidome suggests that zymosan increased the de novo synthesis of sphingolipids without change in the C14–C18:C20–C26 ceramide ratio. At 16 h post-injection, glycosylceramides remained higher in treated than in control mice. A minor effect of zymosan was observed in plasma, whereas sphinganine, dihydrosphingomyelins, and monohexosylceramides were significantly increased in the spleen 16 h post-injection. The consequences of the observed changes in the sphingolipidome remain to be established.

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Spatial Organization of Dectin-1 and TLR2 during Synergistic Crosstalk Revealed by Super-resolution Imaging

Cited by 3 publications

References 51 publications

The Dectin-1 and Dectin-2 clusters: C-type lectin receptors with fundamental roles in immunity

The Dectin-1 and Dectin-2 clusters: C-type lectin receptors with fundamental roles in immunity

Nanocluster-Mediated Signaling Crosstalk between FcγR and TLR4 in Macrophage Inflammatory Responses

Zymosan-Induced Murine Peritonitis Is Associated with an Increased Sphingolipid Synthesis without Changing the Long to Very Long Chain Ceramide Ratio

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