Activated niacin receptor HCA2 inhibits chemoattractant-mediated macrophage migration via Gβγ/PKC/ERK1/2 pathway and heterologous receptor desensitization

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.

FPR1 mediates the tumorigenicity of human cervical cancer cells

“…Activated FPR1 induces the activation of a series of regulatory molecules, including p38, MAPK and ERK1/2, as well as many transcription factors, such as NF-κB, STAT3 and HIF-1α, to promote cancer cell proliferation, invasion and migration. 11 , 13 , 31 , 32 All the data demonstrate that FPR1 agonists within tumor cell microenvironment induce several vital signaling pathways that promote tumorigenesis. We focused on the activation and NF-κB translocation into the cell nucleus to regulate the synthesis and secretion of inflammatory factors.…”

Nicotinic acid suppresses sebaceous lipogenesis of human sebocytes via activating hydroxycarboxylic acid receptor 2 (HCA2)

“…Indeed, as discussed above, NA appears to have negligible effects on the immune behaviour of human sebocytes (Figure ), but through direct actions on professional immune cells, eg macrophages, it still has the potential to exert beneficial effects in acne. Moreover, sebocytes were shown to regulate skin immune processes not only via direct cytokine, chemokine and adipokine release, but also by the composition of the produced sebum .…”

Understanding the Holobiont: How Microbial Metabolites Affect Human Health and Shape the Immune System

“…FFAR2, FFAR3 and HCAR2 all signal through heterotrimeric G i/o proteins. FFAR2 is additionally capable of utilizing G q proteins, but physiological coupling of FFAR2 and G q has only been observed in enteroendocrine L cells (a subset of which, interestingly, expresses OR51E2) (Brown et al, 2003; Fleischer et al, 2015; Le Poul et al, 2003; Nilsson et al, 2003; Y. Shi et al, 2017; Tolhurst et al, 2012; Tunaru et al, 2003; Wise et al, 2003).…”