Abstract
The niacin receptor HCA2 is implicated in controlling inflammatory host responses with yet poorly understood mechanistic basis. We previously reported that HCA2 in A431 epithelial cells transduced Gβγ-protein kinase C- and Gβγ-metalloproteinase/EGFR-dependent MAPK/ERK signaling cascades. Here, we investigated the role of HCA2 in macrophage-mediated inflammation and the underlying mechanisms. We found that proinflammatory stimulants LPS, IL-6 and IL-1β up-regulated the expression of HCA2 on macrophages. Niacin significantly inhibited macrophage chemotaxis in response to chemoattractants fMLF and CCL2 by disrupting polarized distribution of F-actin and Gβ protein. Niacin showed a selected additive effect on chemoattractant-induced activation of ERK1/2, JNK and PI3K pathways, but only the MEK inhibitor UO126 reduced niacin-mediated inhibition of macrophage chemotaxis, while activation of ERK1/2 by EGF alone did not inhibit fMLF-mediated migration of HEK293T cells co-expressing HCA2 and fMLF receptor FPR1. In addition, niacin induced heterologous desensitization and internalization of FPR1. Furthermore, niacin rescued mice from septic shock by diminishing inflammatory symptoms and the effect was abrogated in HCA2−/− mice. These results suggest that Gβγ/PKC-dependent ERK1/2 activation and heterologous desensitization of chemoattractant receptors are involved in the inhibition of chemoattractant-induced migration of macrophages by niacin. Thus, HCA2 plays a critical role in host protection against pro-inflammatory insults.
Highlights
The niacin receptor hydroxy-carboxylic acid receptor 2 (HCA2) is implicated in controlling inflammatory host responses with yet poorly understood mechanistic basis
We demonstrate that HCA2 on macrophages is significantly up-regulated by LPS, IL-6 or IL-1βand mediates an inhibitory activity of niacin on chemoatractant-induced macrophage migration
In an attempt to clarify the mechanisms of niacin-mediated inhibition of macrophage chemotaxis, we found that overexpression of ERK2 led to a significant decrease in fMLF-induced chemotaxis of HEK293T cells co-transfected with HCA2 and the high affinity fMLF receptor FPR1 (Fig. 5C), suggesting that as a negative regulator, niacin-induced activation of the ERK1/2 signaling pathway may contribute to the inhibition of fMLF-induced chemotaxis of RAW264.7 cells and of HEK293T cells expressing FPR1
Summary
The niacin receptor HCA2 is implicated in controlling inflammatory host responses with yet poorly understood mechanistic basis. Niacin rescued mice from septic shock by diminishing inflammatory symptoms and the effect was abrogated in HCA2−/− mice These results suggest that Gβγ/PKC-dependent ERK1/2 activation and heterologous desensitization of chemoattractant receptors are involved in the inhibition of chemoattractant-induced migration of macrophages by niacin. The notion that the beneficial cardiovascular effects of niacin are linked to its antilipolytic activity via HCA2 was recently challenged by the observation that niacin exerts its activity on plasma cholesterol and triglyceride levels independently of HCA2-mediated anti-lipolytic activity and by findings that synthetic HCA2 agonists do not alter HDL-cholesterol levels in human leading to inhibition of lipolysis[17]. Our study revealed a novel molecular mechanism of HCA2 in controlling inflammatory responses
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
