We did however observe that niacin

We did, however, observe that niacin treatment impaired DC accumulation in skin-draining lymph nodes (Fig. 2). Attenuated adaptive immunity, assessed using a contact hypersensitivity assay (Fig. 4), was observed, as would be expected from impaired DC accumulation in lymph nodes, though other mechanisms may also contribute to reduced hypersensitivity. Surprisingly, impaired DC accumulation was not reversed by inhibition of prostaglandin synthesis (Fig. 5) or genetic deficiency of GPR109A (Fig. 6). Collectively, these results imply that niacin-mediated reductions in DC accumulation within lymph nodes must be due to a mechanism of action altogether separate from skin flushing and other activities mediated by GPR109A (Offermanns 2006). Importantly, DC migration was significantly suppressed in both apoE−/− and wild-type mice fed high fat or chow diets supplemented with niacin as compared to appropriate control animals, suggesting migration suppression is a universal phenomenon unrelated to underlying atherosclerosis per se. Walters et al. recently described that niacin signaling via a beta-arrestin 1 dependent pathway induces release of prostaglandin precursors leading to flushing (Walters et al. 2009). Interestingly, however, beta-arrestin null mice still retain anti-lipolytic activity, consistent with the idea that niacin can lead to activation of more than one signaling pathway (Walters et al. 2009). The downstream mediators that account for how niacin impairs accumulation of lymph-trafficking DCs in skin-draining lymph nodes remain to be elucidated. Feeding niacin in the manner that we have used supplies high levels of both major forms of niacin, nicotinic AICAR phosphate sale and nicotinamide. Only nicotinic acid raises HDL levels (Altschul et al. 1955), but it remains possible that nicotinamide contributes to other protective effects when niacin is used clinically. In future studies, it will be important to determine if impaired DC mobilization is a consequence of other forms of niacin, especially nicotinamide, rather than nicotinic acid that binds to GPR109A. For example, nicotinamide inhibits NFκB and MAPK activation in skin keratinocytes in vitro (Grange et al. 2009) and may underlie the effectiveness of nicotinamide in treating acne. As NFκB signaling drives DC migration, its inhibition in vivo would be expected to produce the results we observed. In summary, we have identified a novel action of high-dose niacin therapy in mice—the inhibition of DC accumulation in lymph nodes after their mobilization through lymphatic vessels. We furthermore demonstrated that this action was independent of the known receptor for nicotinic acid GPR109A. Though we did not observe that niacin impacted atherosclerotic directly in the same setting where it inhibits DC mobilization, we nonetheless suggest that it is possible that longer term analyses might reveal an impact on plaques or that disease protection that persists after therapy is lifted (Canner et al. 1986) might be related to immune modulation. Thus, it is now of interest to determine if this novel action of niacin is relevant in humans and if it confers protection in cardiovascular disease or in autoimmune diseases wherein overzealous DC activation of T cells has been observed. Conversely, it is possible that this action is detrimental and restoring DC migration during treatment would advance the efficacy of niacin in treating disease.
Acknowledgements We are grateful to Andrew Taggart at Merck for many helpful discussions and the gift of apoE−/− GPR109A−/− mice. We thank Andrew Platt for critical reading and discussion of the manuscript. This work was supported by the Cordaptive Investigator-Initiated Study Program (IISP) from Merck and Co., Inc., and NIH grant AI061741 to Gwendalyn J. Randolph, a Ruth L. Kirschstein National Research Service Award F32HL096291 to Molly A. Ingersoll, and Stephane Potteaux was supported in part by Fondation pour la Recherche Medicale (France) and a 2007 Norman Alpert Visiting Scientist Award from the European Society of Cardiology/American Heart Association.