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

Abstract

C-type lectin-like receptors (CLRs) represent a family of transmembrane pattern recognition receptors, expressed primarily by myeloid cells. They recognize not only pathogen moieties for host defense, but also modified self-antigens such as damage-associated molecular patterns released from dead cells. Upon ligation, CLR signaling leads to the production of inflammatory mediators to shape amplitude, duration and outcome of the immune response. Thus, following excessive injury, dysregulation of these receptors leads to the development of inflammatory diseases. Herein, we will focus on four CLRs of the "Dectin family," shown to decode the immunogenicity of cell death. CLEC9A on dendritic cells links F-actin exposed by dying cells to favor cross-presentation of dead-cell associated antigens to CD8⁺ T cells. Nevertheless, CLEC9A exerts also feedback mechanisms to temper neutrophil recruitment and prevent additional tissue damage. MINCLE expressed by macrophages binds nuclear SAP130 released by necrotic cells to potentiate pro-inflammatory responses. However, the consequent inflammation can exacerbate pathogenesis of inflammatory diseases. Moreover, in a tumor microenvironment, MINCLE induces macrophage-induced immune suppression and cancer progression. Similarly, triggering of LOX-1 by oxidized LDL, amplifies pro-inflammatory response but promotes tumor immune escape and metastasis. Finally, CLEC12A that recognizes monosodium urate crystals formed during cell death, inhibits activating signals to prevent detrimental inflammation. Interestingly, CLEC12A also sustains type-I IFN response to finely tune immune responses in case of viral-induced collateral damage. Therefore, CLRs acting in concert as sensors of injury, could be used in a targeted way to treat numerous diseases such as allergies, obesity, tumors, and autoimmunity.

Keywords: C-type lectin-like receptors; cross-presentation; dead cells; sterile inflammation; tissue injury.

Figure 1

DAMPs recognition by C-type lectin-like receptors and signaling pathways C-type lectin-like receptors (CLRs) of the “Dectin family” recognize not only pathogen-associated molecular patterns (PAMPs), but also various self-derived ligands such as damage-associated molecular patterns (DAMPs). This recognition triggers activation of immune-receptor tyrosine-based activation motif (ITAM), leading to the recruitment and activation of SYK family kinases. Subsequent activation of the Card9–Bcl10–Malt1 complex through SYK induces NF-κB activation and gene transcription of various chemokines and cytokine (CLEC4E alias MINCLE). Alternatively, CLEC4E can also signal through PLCγ2 to induce the calcineurin/NFAT pathway. Alternatively, immune response can be regulated through increase of ROS and IL-1β production (CLEC8A) modifying gene expression and releasing ROS to the extracellular matrix. By contrast, activation of immune-receptor tyrosine-based inhibition motif (ITIM) induces the recruitment and activation of protein tyrosine phosphatases such as SHP-1 and SHP-2 and the dephosphorylation of activation motifs to inhibit cellular activation mediated by other pattern-recognition receptors (PRRs) (CLEC12A). CLEC9A, via Hemi-ITAM (HITAM) plays a key role in CD8⁺ T cell cross-priming. In addition, CLEC9A can activate SHP-1 to exert inhibitory feedback and restrain excessive immune response.