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.

CRUP: A comprehensive framework to predict condition-specific regulatory units

“…Additionally, we performed a pathway analysis on all putative target genes that are correlated with differentially active enhancers in the affected mice using the Kyoto Encyclopedia of Genes and Genomes (KEGG) (Kanehisa and Goto, 2000;Kanehisa et al, , 2017, a curated database of molecular pathways and disease signatures (see Section 5.13 for details). Genes in the top five resulting KEGG pathways (see Table 1) have been previously associated with rheumatoid arthritis (Szekanecz et al, 2010;Vogelpoel et al, 2015;Chiffoleau, 2018;French and Yokoyama, 2004;Bergler-Czop et al, 2016). A complete list of all gene-enhancer pairs and their associated top five KEGG pathway can be found in Table S6.…”

Pinpointing a potential role for CLEC12B in cancer predisposition through familial exome sequencing

“…CLEC12B is a member of the C‐type lectin‐like receptor (CTLR) family, which is involved in both innate and adaptive immunity and controls homeostasis and tissue injury. CTLRs act as antigen‐uptake receptors for internalization and presentation to T cells and signal through multiple pathways to produce pro‐ or anti‐inflammatory cytokines and chemokines . CLEC12B is a myeloid CTLR within the Dectin‐1 cluster, which encodes six additional members: CLEC7A , CLEC8A , CLEC12A , CLEC1A , CLEC9A , and CLEC1B , all located on chromosome 12p13.2 .…”

“…CTLRs act as antigen-uptake receptors for internalization and presentation to T cells and signal through multiple pathways to produce pro-or anti-inflammatory cytokines and chemokines. [16][17][18] CLEC12B is a myeloid CTLR within the Dectin- Table S3.…”

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).…”