Cutting Edge: CLEC5A Mediates Macrophage Function and Chronic Obstructive Pulmonary Disease Pathologies

Abstract

Chronic Obstructive Pulmonary Disease (COPD) is a devastating disease with no effective therapies. We investigated the role of the C-type lectin receptor, CLEC5A, in macrophage activation and pulmonary pathogenesis in a mouse model of COPD. We demonstrate that CLEC5A is expressed on alveolar macrophages in mice exposed long-term to cigarette smoke (CS) and in human smokers. We also show that CLEC5A-mediated activation of macrophages enhanced cytokine elaboration alone, and in combination with LPS or GM-CSF in CS-exposed mice. Furthermore, using Clec5a-deficient mice, we demonstrate that CS-induced macrophage responsiveness is mediated by CLEC5A and CLEC5A is required for the development of inflammation, proinflammatory cytokine expression and airspace enlargement. These findings suggest a novel mechanism that promotes airway inflammation and pathologies in response to CS exposure and identifies CLEC5A as a novel target for the therapeutic control of COPD pathogenesis.

m6A RNA methylation regulators could contribute to the occurrence of chronic obstructive pulmonary disease

“…This study identified 27 key genes associated with the occurrence of COPD by WGCNA and differential expression analysis in three groups of data sets. These findings are consistent with the previous results that MUCL1, UCHL1, CABYR, CYP1B1, AHRR, AKR1B10, SLC7A11, ST3GAL4‐AS1, GPX2, LOC344887, EGF, CLEC5A, CCL2, MMP12, PLA2G7, GAD1, CYP1A1 and SPP1 were up‐regulated in a variety of samples from COPD or COPD‐related mice model, including peripheral blood mononuclear cells, large and small airway epithelium, quadriceps, blood, and the lung of mouse and human, as well as involved in the occurrence of COPD (Table ) 15,34–48 . GO and KEGG pathway enrichment analyses showed that CYP1B1, CYP1A1, SLC7A11, AKR1B10, AHRR, ALDH3A1 and GPX2 were involved in multiple biological processes related to metabolism of exogenous and endogenous stimulus, and metabolism of xenobiotics by cytochrome P450 signalling pathway, suggesting that the dysregulated expression of these genes might affect the development processes of COPD by influencing the above biological processes and signalling pathway.…”

“…23 as well as involved in the occurrence of COPD (Table S2). 15,[34][35][36][37][38][39][40][41][42][43][44][45][46][47][48] GO and KEGG pathway enrichment analyses showed that CYP1B1, In conclusion, for the first time, our study systematically demonstrated the expression and potential functions of m6A RNA methylation regulators in COPD. The expressions of IGF2BP3, FTO, METTL3…”

Identification of gene expression predictors of occupational benzene exposure

“…It is expressed on human inflammatory macrophages in vivo [ 58 ] and is a critical receptor for some viruses [ 59 – 62 ], and bacteria [ 63 ] and mediates innate immunity inflammatory response. CLEC5A is also expressed on alveolar macrophages in mice exposed long-term to cigarette smoke (CS), as well as in human smokers, and it mediates macrophage function and chronic obstructive pulmonary disease pathology in mice [ 64 ]. NF-kappa-B is a pleiotropic transcription factor present in most cell types and is activated by various stimuli such as cytokines, oxidant-free radicals, ultraviolet irradiation, and bacterial or viral products.…”

Transcriptomic Analysis of Respiratory Tissue and Cell Line Models to Examine Glycosylation Machinery during SARS-CoV-2 Infection

“…Gene expression pattern and the induced network model analysis results of the inflammatory CLECs and the anti-inflammatory SIGLECs mentioned in the current report is in alignment with the clinical phenotype of cytokine storm, neutrophil extracellular trap formation as well as the functional exhaustion of lymphocytes reported in severe cases of COVID-19 patients [ 46 , 47 , 48 , 49 , 78 , 79 ]. Increased gene expression pattern of inflammatory CLECs in the nasopharyngeal samples may represent the molecular markers of innate immune function of airway epithelial cells and immune components [ 80 , 81 ]. However, dual anti-inflammatory function have also been attributed to few CLECs such as CLEC7A (Dectin-1) and CLEC4E (Mincle) depending on the ligand and its interaction with the pattern recognition receptors [ 82 ].…”