Niacin benefits infections

Our featured image is a reminder that the niacin receptor is a member of the G protein coupled receptor family.  These receptors talk to each other via α subunits.

Niacin is the other two thirds of Cu(I)NA2., a cuprous niacin supplement available on the market.  Most healthcare providers are probably aware of niacin’s many functions.

A big unknown for us is if Cu(I)NA2 can even bind to the niacin receptor.  If nothing else, the other two thirds modulate the immune system.

  1. Niacin is a  precursor to NAD/NADH2, an H+ / electron carrier in numerous biochemical reactions.
  2. Niacin in high doses causes  dilation of the skin’s vasculature in a  response called “flush.”
  3. High doses of niacin are available in prescription form as Niaspan® and its generic equivalent “niacin ER” to lower  low density lipoprotein (LDL) cholesterol

Niacin receptors in neutrophils and more

Apart from being a precursor of NADH2, niacin has direct physiological actions on its  high and low affinity receptors

  1. NIACR1 is also known as the hydroxy carboxylic acid receptor (HCA2) GPR109A, HM74a, HM74b.NIACR2.
  2. NIACR2 is also known as HCA3 and GPR109B.  It is the low affinity receptor that is activated by amounts of niacin not normally found in the diet.

Protein Atlas has compiled some nice data on the mRNA expression of GPR109A in blood cells.

NiacinInfections1
Top. Consensus mRNA expression of GPR109A, a niacin receptor, in blood cells. Bottom Data for dendritic cells, microglia, and macrophage are harder to obtain when they migrate into the tissue site of an infection. GPR109A expression in macrophage may be induced by lipopolysaccharide (LPS) from Gram negative bacteria.

Niacin receptors and cAMP

A 2008 study of Kostylina demonstrated that niacin promotes apoptosis, programmed cell death,  in mature but not immature neutrophils.  This action is mediated by the GPR109A G-protein coupled receptor.  G-protein coupled receptors may stimulate or inhibit the enzyme adenylyl cyclase.  AC converts cellular ATP to the second messenger cyclic AMP (cAMP).  Note the cyan colored  βγ subunit.  These will come into the discussion of potential niacin signalling in macrophage.

NiacinInfections2
A Niacin GPR109A pathways to vasodilation seen in “flush” B G-protein coupled receptors responsible for pro-survival pathways in neutrophils couple to Gs that activates adenylyl cyclase. The niacin receptor GPR109A couples with Gi that inhibits adenylyl cyclase (AC).

G protein coupled receptor cross talk

The authors did not discuss which G-protein coupled receptor on neutrophils might be simulating adenylyl cyclase by way of a Gs subunit.  The interleukin-2 and PGE2 receptors are G-protein coupled receptors that may stimulate neutrophils.

Niacin, GPR109A, and macrophages

Inflammatory mediators LPS ( Gram negative bacteria), zymosan (polysaccharide in  yeast, fungi),  lipoteichoic acid (LTA, Gram positive bacteria), polyinosine-polycytidylic acid (poly I:C, viruses) induce GRP109A in cultured marcrophage.  (Feingold 2014).   LPS was able to increase GPR109A mRNA up to 80x in less than 24 hours.  Niacin binding to GRP109A receptor may be a means of turning off the initial, innate immune response to pathogens.

Niacin inhibits macrophages by decreasing cAMP

Zandi-Nejad and coworkers (2013) examined the role of niacin on macrophage function.  Their primary focus was the role of macrophage in atherosclerosis rather than infectious diseases.  The”cytokine storm“, also known as cytokine release syndrome, has gained a lot of attention as a morbidity factor in COVID-19.

  1. Phagocytosis and chemotaxis  of blood wild type HCAR2+/+  and  HCAR2-/-   knock out mouse bone marrow derived marcophage (BBM) was shown to be decreased by nicotinic acid.  The HCAR2 gene codes for the GRP9A protein.
  2. LPS induction of cytokines TNFα, IL-6, IL-12p40, and IL-1β was measured in
  3. HCAR2+/+  and  HCAR2-/-   BBM.  Niacin lowered mRNA transcripts of all of these cytokines after 48 hours of exposure to LPS in the wild type but not in the BBM lacking the GPR109A receptors.

Zandi-Nejad and coworkers (2013) remarked that their results differed from those of Rossi (1998) in that cAMP increases inhibited macrophage.  Shi (2017) suggested that niacin macrophage inhibition had more to do with the βγ subunit of heterotrimeric G proteins acting on protein kinase C.

A look back, cAMP and macrophage activity

Rossi (1998) demonstrated that intracellular cAMP decreased the ability of preipheral blood monocyte derived macrophage to phagocytize apoptotic neutrophils but not opsonized red blood cells.  These  authors also found that PGE2 to be a strong inducer of cAMP.

A look ahead at recent publications

Negreiros-Lima and coworkers (2020) have pushed the boundaries of earlier studies.  These authors used a non-hydrolyzable analog of cAMP, db-cAMP to activate protein kinase A pathways.  They addressed ways that cAMP modulates the M1 (pro inflammatory) to M2 (anti-inflammatory) transition.  To make matters more complicated, they introduced the M2 subsets: M2a, M2b and M2c.   We have no idea if the GRP109A receptor is expressed in all of these developmental stages.  An additional new term is  “effectocytosis” the clearance of neutrophils undergoing apoptosis.

References

Bühler S, Frahm J, Liermann W, Tienken R, Kersten S, Meyer U, Huber K, Dänicke S.(2018) Effects of energy supply and nicotinic acid supplementation on phagocytosis and ROS production of blood immune cells of periparturient primi- and pluriparous dairy cows. Res Vet Sci.116:62-71

Guyton J., Campbell K., Lakey W. (2015) Niacin: Risk Benefits and Role in Treating Dyslipidemias. In: Garg A. (eds) Dyslipidemias. Contemporary Endocrinology. Humana Press, Totowa, NJ

Feingold KR, Moser A, Shigenaga JK, Grunfeld C.(2014) Inflammation stimulates niacin receptor (GPR109A/HCA2) expression in adipose tissue and macrophages. J Lipid Res. 2014 Dec;55(12):2501-8. Link

Kostylina G, Simon D, Fey MF, Yousefi S, Simon HU.(2008) Neutrophil apoptosis mediated by nicotinic acid receptors (GPR109A). Cell Death Differ.15(1):134-42  Link

Negreiros-Lima GL, Lima KM, Moreira IZ, Jardim BLO, Vago JP, Galvão I, Teixeira LCR, Pinho V, Teixeira MM, Sugimoto MA, Sousa LP. (2020) Cyclic AMP Regulates Key Features of Macrophages via PKA: Recruitment, Reprogramming and Efferocytosis. Cells. 9(1). pii: E128. Link

Rossi AG, McCutcheon JC, Roy N, Chilvers ER, Haslett C, Dransfield I. (1998) Regulation of macrophage phagocytosis of apoptotic cells by cAMP. J Immunol. 160(7):3562-8.Link

Shi Y, Lai X, Ye L, Chen K, Cao Z, Gong W, Jin L, Wang C, Liu M, Liao Y, Wang JM, Zhou N. (2017) Activated niacin receptor HCA2 inhibits chemoattractant-mediated macrophage migration via Gβγ/PKC/ERK1/2 pathway and heterologous receptor desensitization. Sci Rep. 2017 Feb 10;7:42279 Link

Zandi-Nejad K, Takakura A, Jurewicz M, Chandraker AK, Offermanns S, Mount D, Abdi R (2013) The role of HCA2 (GPR109A) in regulating macrophage function. FASEB J. 27(11):4366-74. Link

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