Abstract
C-Type lectin receptor 5A (CLEC5A) is a spleen tyrosine kinase- (Syk-) coupled pattern recognition receptor expressed on myeloid cells and involved in the innate immune response to viral and bacterial infections. Activation of the CLEC5A receptor with pathogen-derived antigens leads to a secretion of proinflammatory mediators such as TNF-α and IL-6 that may provoke a systemic cytokine storm, and CLEC5A gene polymorphisms are associated with the severity of DV infection. In addition, the CLEC5A receptor was mentioned in the context of noninfectious disorders like chronic obstructive pulmonary disease (COPD) or arthritis. Altogether, CLEC5A may be considered as an innate immune checkpoint capable to amplify proinflammatory signals, and this way contributes to infection or to aseptic inflammation. In this study, we determined CLEC5A receptor expression on different macrophage subsets (in vitro and ex vivo) and the functional consequences of its activation in aseptic conditions. The CLEC5A surface expression appeared the highest on proinflammatory M1 macrophages while intermediate on tumor-associated phenotypes (M2c or TAM). In contrast, the CLEC5A expression on ex vivo-derived alveolar macrophages from healthy donors or macrophages from ovarian cancer patients was hardly detectable. Targeting CLEC5A on noninflammatory macrophages with an agonistic α-CLEC5A antibody triggered a release of proinflammatory cytokines, resembling a response to dengue virus, and led to phenotypic changes in myeloid cells that may suggest their reprogramming towards a proinflammatory phenotype, e.g., upregulation of CD80 and downregulation of CD163. Interestingly, the CLEC5A agonist upregulated immune-regulatory molecules like CD206, PD-L1, and cytokines like IL-10, macrophage-derived chemokine (MDC/CCL22), and thymus and activation chemokine (TARC/CCL17) which are associated with an anti-inflammatory or a protumorigenic macrophage phenotype. In the absence of concomitant pathogenic or endogenous danger signals, the CLEC5A receptor activation did not amplify an autologous T cell response, which may represent a protective innate mechanism to avoid an undesirable autoimmune adaptive response.
Highlights
CLEC5A known as myeloid DAP12-associating lectin-1 (MDL-1) is a myeloid spleen tyrosine kinase- (Syk-)coupled pattern recognition receptor which preferentially binds to glycans highly expressed on the surface of pathogens
In order to investigate the role of the CLEC5A receptor in a normal healthy condition, i.e., in the absence of pathogens reported to interact with CLEC5A, we needed to identify a CLEC5A-selective tool, e.g., a monoclonal Ab that exclusively activates CLEC5A in myeloid cells without possible involvement of other surface receptors
From alternative tools to trigger CLEC5A activation, for instance, from deactivated dengue viral particles, because such tools could function as a pathogen-associated molecular pattern (PAMP) and in consequence - activate the CLEC5A receptor and other receptors reported to interact with dengue virus (DV), like DC_SIGN or mannose receptors [24]
Summary
CLEC5A known as myeloid DAP12-associating lectin-1 (MDL-1) is a myeloid Syk-coupled pattern recognition receptor which preferentially binds to glycans highly expressed on the surface of pathogens. CLEC5A can form multivalent heterocomplexes with other C-type lectins, like DC-SIGN or mannose receptor, and with Toll-like receptors (TLR). The CLEC5A receptor activation results in the downstream signaling via DAP12 and Syk (as reviewed in [1]). The ligand for CLEC5A was identified as terminal fucose and mannose moieties of viral glycans, expressed by dengue virus (DV) [7], Japanese encephalitis virus [8] or type A influenza virus [9]. Sung et al reported that CLEC5A could interact with exosomes released from activated platelets, the ligand responsible for this interaction has not been identified [11]. Joyce-Shaikh et al mentioned galectin-9 (Gal9) as a sterile ligand for CLEC5A and proposed a model of Gal9-mediated interaction between CLEC5A-expressing myeloid cells and Gal9-binding T cells [12]
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