Flexible Signaling of Myeloid C-Type Lectin Receptors in Immunity and Inflammation

Abstract

Myeloid C-type lectin receptors (CLRs) are important sensors of self and non-self that work in concert with other pattern recognition receptors (PRRs). CLRs have been previously classified based on their signaling motifs as activating or inhibitory receptors. However, specific features of the ligand binding process may result in distinct signaling through a single motif, resulting in the triggering of non-canonical pathways. In addition, CLR ligands are frequently exposed in complex structures that simultaneously bind different CLRs and other PRRs, which lead to integration of heterologous signaling among diverse receptors. Herein, we will review how sensing by myeloid CLRs and crosstalk with heterologous receptors is modulated by many factors affecting their signaling and resulting in differential outcomes for immunity and inflammation. Finding common features among those flexible responses initiated by diverse CLR-ligand partners will help to harness CLR function in immunity and inflammation.

MGL1 Receptor Plays a Key Role in the Control of T. cruzi Infection by Increasing Macrophage Activation through Modulation of ERK1/2, c-Jun, NF-κB and NLRP3 Pathways

“…Protozoa parasites possess numerous glycosylated structures that are capable of activating the innate immune response by binding to pattern recognition receptors (PRRs), such as toll like receptors (TLRs) and CLRs such as the mannose receptor (MR), dendritic cell-specific intercellular adhesion molecule 3-grabbing non-integrin (DC-SIGN), MGL and Dectin-1, among others [2,8]. Previous reports have shown that CLRs cooperate with TLRs to activate intracellular signaling pathways upon sensing pathogen-derived antigens [9][10][11]. For example, Dectin-1 and MR expressed in Mφ play a crucial role in the microbicidal response by inducing reactive oxygen species (ROS) production against the protozoan Leishmania infantum [12].…”

DNGR-1, a Dendritic Cell-Specific Sensor of Tissue Damage That Dually Modulates Immunity and Inflammation

“…These results indicate that DNGR-1 may specifically dampen heterologous signaling pathways. Indeed, the capacity of CLRs to cross-talk with heterologous receptors is well-known (52,53). As CXCL2 is one of the main drivers of neutrophil attraction to inflammation sites upon C. albicans infection (54,55), administration of pepducin, a peptide that blocks signal transduction via CXCR2, the main receptor for CXCL2, reverts the increased neutrophil recruitment in DNGR-1-deficient mice (6).…”

C-Type Lectin-Like Receptors: Head or Tail in Cell Death Immunity

“…This leads to activation of NF-κB pathway and various cellular responses such as the production of reactive oxygen species (ROS) and the expression of diverse cytokines and chemokines to regulate both innate and adaptive immune responses (19,(28)(29)(30)(31)(32)(33). In contrast, some CLRs contain an immunoreceptor tyrosine-based inhibitory motif (ITIM) that induces the recruitment of tyrosine phosphatases such as Src homology region 2 domain-containing phosphatase (SHP)−1 or −2, to negatively regulate the activity of activating signaling pathways (34)(35)(36)(37). At last, some CLRs have neither ITAM nor ITIM domains and their signaling is either uncharacterized or utilizes alternative pathways such as via the serine/threonine kinase RAF-1 (17,35,38,39).…”

“…However, classification of CLRs as activating or inhibitory receptors is not as simple. A same CLR can according to the ligand (physical nature, affinity, avidity) or the environment, integrate distinct positive and negative signals, to shape immune response in complex scenarios (37). In addition, sensing of tissue damage by CLRs can complement detection of pathogens.…”