Vitamin B6 Prevents IL-1β Protein Production by Inhibiting NLRP3 Inflammasome Activation

Abstract

Edited by Luke O'NeillVitamin B6 includes six water-soluble vitamers: pyridoxal (PL), pyridoxamine (PM), pyridoxine (PN), and their phosphorylated forms. Pyridoxal 5-phosphate (PLP) is an important cofactor for many metabolic enzymes. Several lines of evidence demonstrate that blood levels of PLP are significantly lower in patients with inflammation than in control subjects and that vitamin B6 has anti-inflammatory effects, with therapeutic potential for a variety of inflammatory diseases. Although one of our group previously demonstrated that PL inhibits the NF-B pathway, the molecular mechanism by which vitamin B6 suppresses inflammation is not well understood. Here, we showed that both PL and PLP suppressed the expression of cytokine genes in macrophages by inhibiting Toll-like receptor (TLR)-mediated TAK1 phosphorylation and the subsequent NF-B and JNK activation. Furthermore, PL and PLP abolished NLRP3-dependent caspase-1 processing and the subsequent secretion of mature IL-1␤ and IL-18 in LPS-primed macrophages. In contrast, PM and PN had little effect on IL-1␤ production. PLP, but not PL, markedly reduced the production of mitochondrial reactive oxygen species (ROS) in peritoneal macrophages. Importantly, PL and PLP reduced IL-1␤ production induced by LPS and ATP, or by LPS alone, in mice. Moreover, PL and PLP protected mice from lethal endotoxic shock. Collectively, these findings reveal novel anti-inflammatory activities for vitamin B6 and suggest its potential for preventing inflammatory diseases driven by the NLRP3 inflammasome.

Vitamin B6 inhibits macrophage activation to prevent lipopolysaccharide‐induced acute pneumonia in mice

“…First, we identified that VitB6 increases AMPK Thr172 phosphorylation in An issue needs to be discussed is that VitB6 has been reported to inhibit inflammation via suppressing NF-κB activation and NLRP3-mediated caspase-1 activation because PLP is able to inhibit the phosphorylation of TAK1 and JNK induced by LPS as well as IKK-IκBα pathway. 9 However, our data reveal that VitB6 inhibits inflammation through AMPK Thr172 phosphorylation followed by DOK3 activation. In consistency, the inactivation of AMPK promotes a state of increased inflammatory responsiveness in murine macrophages, which is demonstrated by activating NF-κB-dependent gene expressions, as well as caspase-1 activation and IL-1β maturation.…”

“…An issue needs to be discussed is that VitB6 has been reported to inhibit inflammation via suppressing NF‐κB activation and NLRP3‐mediated caspase‐1 activation because PLP is able to inhibit the phosphorylation of TAK1 and JNK induced by LPS as well as IKK‐IκBα pathway . However, our data reveal that VitB6 inhibits inflammation through AMPK Thr172 phosphorylation followed by DOK3 activation.…”

“…Studies from others and us have shown that low plasma PLP concentrations are associated with increased risk of cardiovascular diseases and supplementation of VitB6 lowers serum levels of IL‐6 and TNF‐α in patients with rheumatoid arthritis . VitB6 has also been demonstrated to suppress IL‐1β productions . Clinical trials have found that VitB6 alleviates Alzheimer's disease and Parkinson's disease .…”

Gut microbiota and inflammation in chronic kidney disease and their roles in the development of cardiovascular disease

“…As suggested, the gut microbiota can establish efficient crosstalk with the rest of the body through a number of mediators. Interestingly, the metabolic end products of the [41,42] SCFAs [46] miRNAs [56] Indoxyl sulfate [43,44] NO [47] b Bile acids [50] TMAO [45] Vitamin K [51] N E [ 63] Oxalate [48,49] Vitamin B complex [17,[52][53][54] ANS [66,99] Serotonin [62] Threonine [55] ENS [67] GLP-1 [57] GLP-2 [58] PYY [59] GABA [60,61] ACh [65] Dopamine [64] H 2 S [87,88] a Some of these mediators have both pro-and anti-inflammatory effects…”

“…On the other hand, the activation of the bile acid receptors Farnesoid X Receptor (FXR) and TGR5 have an anti-inflammatory effect [50], chenodeoxycholic acid (CDCA) being the most potent activator of FXR [83] •NE: Activation of the α-adrenergic receptors elicits pro-inflammatory effects while β-adrenergic receptor activity is anti-inflammatory [63] •ANS: The parasympathetic nervous system (PNS) suppresses inflammation via activation of the ACh receptor α7nAChR [66]. On the other hand, the sympathetic nervous system (SNS) can exert both pro-inflammatory (via α 2 -adrenergic receptors) and anti-inflammatory (via β 2 -adrenergic receptors) effects [66], pro-inflammatory properties being more dominant [99] •ENS: The inflammatory effects of ENS depends on the location of the intestinal macrophages they induce; the lamina propria macrophages (LpMs) are inclined to be pro-inflammatory while the muscularis macrophages tend to have an anti-inflammatory phenotype, having the anti-inflammatory β2-adrenoceptors [67] b Even though NO can have pro-inflammatory activity via NF-κB activation, the number of mechanisms leading to its anti-inflammatory effects are more [47] gut microbiota, including p-CS [41,42]; IS [43,44]; trimethylamine-N-oxide (TMAO) [45]; ammonia [24]; SCFAs [46]; NO [47]; oxalate [48,49] and bile acids [50]; vitamin K [51]; vitamin B complex [17,[52][53][54]; threonine [55]; miRNAs [56]; gut hormones such as GLP-1, GLP-2, and peptide YY (PYY) [57][58][59]; neurotransmitters such as γ-aminobutyric acid (GABA), serotonin, norepinephrine (NE), dopamine (DA), and acetylcholine (Ach) [60][61][62][63][...…”