Niacin inhibits skin dendritic cell mobilization in a GPR109A independent manner but has no impact on monocyte trafficking in atherosclerosis

Abstract

High-dose niacin therapy in humans reduces mortality from cardiovascular disease and may also protect against death from other causes, with benefits apparent more than a decade beyond the therapeutic period. Niacin therapy modulates circulating lipids, raising HDL and lowering LDL, but has the unwanted side effect of inducing skin flushing in response to treatment. Skin flushing results from niacin-induced activation of GPR109A and subsequent release of prostaglandins that promote vasodilation. GPR109A may also mediate HDL elevation. Recent data suggest that high-dose niacin may have benefits beyond improved lipid profiles, such as quelling inflammation, suggesting a potential role in immune cell trafficking. To explore effects of niacin on immune cell trafficking independently of its effects on lipid profiles, we took advantage of the fact that niacin therapy does not raise HDL in wild-type or apoE−/− mouse strains. Wild-type and apoE−/− C57BL/6 mice were fed standard chow or high-fat diets supplemented or not with 1% niacin. Against our predictions, this treatment did not modulate monocyte recruitment to or retention within atherosclerotic plaques. By contrast, stimulating the skin of niacin-treated mice with a contact sensitizer revealed impaired dendritic cell accumulation in draining lymph nodes and associated impaired adaptive immunity. Surprisingly, niacin-mediated impaired dendritic cell mobilization could not be reversed by cyclooxygenase inhibitor treatment nor deletion of the niacin receptor GPR109A, suggesting that the effects of niacin on modulating the migration of dendritic cells are not directly linked to skin flushing. Overall, these data suggest the existence of novel pathways triggered by niacin that, through suppression of dendritic cell migration, might impact adaptive immune responses that participate in sustained therapeutic benefits independent of niacin’s cardioprotective capabilities.

Niacin in Cardiovascular Disease: Recent Preclinical and Clinical Developments

“…70 A recent study in mice has shown that short-term niacin treatment impairs dendritic cell accumulation into draining skin lymph nodes, though this was not reversed by prostaglandin synthesis inhibition using the cyclooxygenase inhibitor, naproxen. 71 Furthermore, recent work from our laboratory confirms that the anti-inflammatory effects of niacin treatment in human monocytes in vitro, measured by release of inflammatory mediators such as tumor necrosis factor- α , monocyte chemotactic protein-1, and IL6 persist despite inhibition of PGD 2 . 23…”

The nutrition‐gut microbiome‐physiology axis and allergic diseases

“…114 This suggests an important role for the expression of Migration of DCs to draining lymph nodes in response to contact sensitization was impaired in mice-fed niacin-supplemented diets, an effect unchanged in GPR109a KO mice. 117 Niacin may therefore alter DC migration independently of GPR109a to regulate inflammatory responses.…”

Gut microbiota–derived short-chain fatty acids and kidney diseases

“…In addition, GPR109a is reported to express on gut epithelial cells, adipocytes, macrophages, and dendritic cells, which only respond to butyrate and not to acetate or propionate. 29 – 32 Finally, when it comes to the physiological role as HDAC inhibitors, compared to propionate, butyrate is more potent in terms of pan-inhibitory activity. SCFAs affect the expression of genes with diverse functions by inhibiting the activity of HDAC to exhibit anti-tumor, anti-fibrotic, and anti-inflammatory activities.…”