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The role of HCA2 (GPR109A) in regulating macrophage function.

ABSTRACT: We investigated the novel role of HCA2 (GPR109A) and its ligand nicotinic acid in regulating macrophage function. Hca2 expression in the RAW264.7 murine macrophage cell line is strongly induced by LPS treatment and correlates with the expression of TNF-?. Treatment with 300 ?M nicotinic acid (reported EC50 3 ?M, peak plasma concentration 50-300 ?M), significantly inhibited TNF-?, IL-6, IL-12p40, and IL-1? production (P<0.05) in LPS (1 ng/ml)-stimulated wild-type murine bone marrow-derived macrophages (BMMs) but failed to do so in Hca2(-/-) BMMs. Treatment with nicotinic acid reduced nuclear factor ?B (NF-?B) activation levels by 43% (P<0.03) in wild-type BMMs 6 h after LPS stimulation but not in Hca2(-/-) BMMs. Nicotinic acid significantly inhibited wild-type BMM chemotaxis (P<0.001), but had no effect on the chemotaxis of Hca2(-/-) BMMs. A significant increase in low-density lipoprotein uptake by both wild-type (P<0.006) and Hca2(-/-) BMMs (P<0.03) in response to LPS was observed, which was significantly suppressed by nicotinic acid in wild-type BMMs (P<0.04) but not in Hca2(-/-) BMMs. Our results suggest that the nicotinic acid-HCA2 axis is a novel negative regulator of macrophage activation.

SUBMITTER: Zandi-Nejad K

PROVIDER: S-EPMC3804742 | biostudies-literature | 2013 Nov

REPOSITORIES: biostudies-literature

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The role of HCA2 (GPR109A) in regulating macrophage function.

Zandi-Nejad Kambiz K Takakura Ayumi A Jurewicz Mollie M Chandraker Anil K AK Offermanns Stefan S Mount David D Abdi Reza R

FASEB journal : official publication of the Federation of American Societies for Experimental Biology 20130723 11

We investigated the novel role of HCA2 (GPR109A) and its ligand nicotinic acid in regulating macrophage function. Hca2 expression in the RAW264.7 murine macrophage cell line is strongly induced by LPS treatment and correlates with the expression of TNF-α. Treatment with 300 μM nicotinic acid (reported EC50 3 μM, peak plasma concentration 50-300 μM), significantly inhibited TNF-α, IL-6, IL-12p40, and IL-1β production (P<0.05) in LPS (1 ng/ml)-stimulated wild-type murine bone marrow-derived macrop ...[more]

PMID: 23882124

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Project description:Exposure to diesel exhaust emissions (DEE) is strongly linked to innate immune injury and lung injury, but the role of macrophage chemoattractant CXCL17 in the lung damage caused by DEE exposure remains unclear. In this study, whole-body plethysmography (WBP), inflammatory cell differential count, and histopathological analysis were performed to assess respiratory parameters, airway inflammation, and airway injury in C57BL/6 male mice exposed to DEE for 3 months. qRT-PCR, IHC (immunohistochemistry), and ELISA were performed to measure the CXCL17 expression in airway epithelium or BALF (bronchoalveolar lavage fluid) following DEE/Diesel exhaust particle (DEP) exposure. Respiratory parameters, airway inflammation, and airway injury were assessed in CXCL17-overexpressing mice through adeno-associated virus vector Type 5 (AAV5) infection. Additionally, an in vitro THP-1 and HBE co-culture system was constructed. Transwell assay was carried out to evaluate the effect of rh-CXCL17 (recombinant human protein-CXCL17) on THP-1 cell migration. Flow cytometry and qRT-PCR were conducted to assess the impacts of rh-CXCL17 on apoptosis and inflammation/remodeling of HBE cells. We found that the mice exposed to DEE showed abnormal respiratory parameters, accompanied by airway injury and remodeling (ciliary injury in airway epithelium, airway smooth muscle hyperplasia, and increased collagen deposition). Carbon content in airway macrophages (CCAM), but not the number of macrophages in BALF, increased significantly. CXCL17 expression significantly decreased in mice airways and HBE after DEE/DEP exposure. AAV5-CXCL17 enhanced macrophage recruitment and clearance of DEE in the lungs of mice, and it improved respiratory parameters, airway injury, and airway remodeling. In the THP-1/HBE co-culture system, rh-CXCL17 increased THP-1 cell migration while attenuating HBE cell apoptosis and inflammation/remodeling. Therefore, CXCL17 might attenuate DEE-induced lung damage by recruiting and activating pulmonary macrophages, which is expected to be a novel therapeutic target for DEE-associated lung diseases.

Dataset Information

The role of HCA2 (GPR109A) in regulating macrophage function.

Publications

The role of HCA2 (GPR109A) in regulating macrophage function.

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