C-Type Lectin-Like Receptors As Emerging Orchestrators of Sterile Inflammation Represent Potential Therapeutic Targets

Abstract

Over the last decade, C-type lectin-like receptors (CTLRs), expressed mostly by myeloid cells, have gained increasing attention for their role in the fine tuning of both innate and adaptive immunity. Not only CTLRs recognize pathogen-derived ligands to protect against infection but also endogenous ligands such as self-carbohydrates, proteins, or lipids to control homeostasis and tissue injury. Interestingly, CTLRs act as antigen-uptake receptors via their carbohydrate-recognition domain for internalization and subsequent presentation to T-cells. Furthermore, CTLRs signal through a complex intracellular network leading to the secretion of a particular set of cytokines that differently polarizes downstream effector T-cell responses according to the ligand and pattern recognition receptor co-engagement. Thus, by orchestrating the balance between inflammatory and resolution pathways, CTLRs are now considered as driving players of sterile inflammation whose dysregulation leads to the development of various pathologies such as autoimmune diseases, allergy, or cancer. For examples, the macrophage-inducible C-type lectin (MINCLE), by sensing glycolipids released during cell-damage, promotes skin allergy and the pathogenesis of experimental autoimmune uveoretinitis. Besides, recent studies described that tumors use physiological process of the CTLRs' dendritic cell-associated C-type lectin-1 (DECTIN-1) and MINCLE to locally suppress myeloid cell activation and promote immune evasion. Therefore, we aim here to overview the current knowledge of the pivotal role of CTLRs in sterile inflammation with special attention given to the "Dectin-1" and "Dectin-2" families. Moreover, we will discuss the potential of these receptors as promising therapeutic targets to treat a wide range of acute and chronic diseases.

Keywords: C-type lectin-like receptors; autoimmune diseases; cancer; sterile inflammation; tissue injury.

Figure 1

Schematic representation of various C-type lectin-like receptors (CTLRs) and selected endogenous ligands and signals. CTLRs are composed of an extracellular C-type lectin-like domain able to recognize various endogenous ligands and signal directly, through integral motifs in their cytoplasmic tails or indirectly through association with FcRγ. They can also contain a tri-acidic domain DED or DDD important for phagocytosis. Activation of immune-receptor tyrosine-based activation motif (ITAM) leads to the recruitment and activation of SYK family kinases. Subsequent activation of the CARD9–Bcl10–Malt1 complex through PKδ induces NF-κB activation and gene transcription of various cytokine and chemokines. Furthermore, SYK induces reactive oxygen species production and inflammasome activation via NLRP3 and Caspase 1 leading to IL-1β production. Alternative pathway of signalization independently of SYK has been reported for dendritic cell-associated C-type lectin-1 (DECTIN-1) via RAF-1 to finely regulate NF-κB activation. 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 motifs to inhibit cellular activation mediated by other immunoreceptors.

Figure 2

Dual role of macrophage-inducible C-type lectin (MINCLE) in disease pathogenesis. Recognition of cholesterol sulfate by MINCLE whose expression is increased in plasmacytoid dendritic cells (DC) following skin damage, induces IL-1 α and β secretion, and promotes skin allergy and allergic contact dermatitis. By contrast, MINCLE recognition of spliceosome-associated protein 130 (SAP130) released by necrotic cancer cells leads to tolerogenic tumor-infiltrating macrophage reprogramming in pancreatic ductal adenocarcinoma.