Taurine Antagonizes Macrophages M1 Polarization by Mitophagy-Glycolysis Switch Blockage via Dragging SAM-PP2Ac Transmethylation.

The excessive M1 polarization of macrophages drives the occurrence and development of inflammatory diseases. The reprogramming of macrophages from M1 to M2 can be achieved by targeting metabolic events. Taurine promotes for the balance of energy metabolism and the repair of inflammatory injury, preventing chronic diseases and complications. However, little is known about the mechanisms underlying the action of taurine modulating the macrophage polarization phenotype. In this study, we constructed a low-dose LPS/IFN-γ-induced M1 polarization model to simulate a low-grade pro-inflammatory process. Our results indicate that the taurine transporter TauT/SlC6A6 is upregulated at the transcriptional level during M1 macrophage polarization. The nutrient uptake signal on the membrane supports the high abundance of taurine in macrophages after taurine supplementation, which weakens the status of methionine metabolism, resulting in insufficient S-adenosylmethionine (SAM). The low availability of SAM is directly sensed by LCMT-1 and PME-1, hindering PP2Ac methylation. PP2Ac methylation was found to be necessary for M1 polarization, including the positive regulation of VDAC1 and PINK1. Furthermore, its activation was found to promote the elimination of mitochondria by macrophages via the mitophagy pathway for metabolic adaptation. Mechanistically, taurine inhibits SAM-dependent PP2Ac methylation to block PINK1-mediated mitophagy flux, thereby maintaining a high mitochondrial density, which ultimately hinders the conversion of energy metabolism to glycolysis required for M1. Our findings reveal a novel mechanism of taurine-coupled M1 macrophage energy metabolism, providing novel insights into the occurrence and prevention of low-grade inflammation, and propose that the sensing of taurine and SAM availability may allow communication to inflammatory response in macrophages.

The effect of micro-nutrients on malnutrition, immunity and therapeutic effect in patients with pulmonary tuberculosis: A systematic review and meta-analysis of randomised controlled trials.

OBJECTIVE: Micro-nutrients are closely related to pulmonary tuberculosis (PTB). Most patients with PTB suffer from micro-nutrients deficiency. We aimed to evaluate the efficacy of micro-nutrients support on clinical therapy and chronic inflammation in patients with PTB. METHODS: We searched Pubmed, Springer link, Web of Science, Cochrane, Wan Fang and CNKI databases for randomised controlled trials (RCTs). The patients with anti-TB treatments were divided into two groups, the control group with nutritional advice or placebo, and the experimental group with micro-nutrients support for more than 2 weeks. Two reviewers conducted data extraction and quality assessment of the studies independently, and ReviewManager 5.2 software was used to input and analyse the data. The dichotomous variable was expressed in the risk ratios (RRS) and 95% CI, the continuous data were expressed in the mean difference (MD) and 95% CI, and the heterogeneity of subgroup was evaluated by I (Kerantzas and Jacobs, Jr., 2017) [2] test. RESULTS: A total of 13 trials (2847 participants) were included. First, micro-nutrients improved sputum smears or culture negative conversion rates (OR 0.16 0.03-0.77, 2.29; MD -2.36, -4.72~-0.01, z = 1.97). Meanwhile, micro-nutrients support increased lymphocytes and decreased leukocytes, neutrophils, CRP and ESR (MD 0.20, 0.06-0.35, z = 2.78; MD -0.42, -0.65~-0.18, z = 3.48; MD -0.66, -1.12~-0.20, z = 2.82). However it had not impact on body weight, MUAC, haemoglobin, albumin or monocytes (p > 0.05). CONCLUSION: Micro-nutrients support can reduce chronic inflammation and improve sputum smears or culture conversions to contribute to anti-TB treatment.

Methionine-Mediated Protein Phosphatase 2A Catalytic Subunit (PP2Ac) Methylation Ameliorates the Tauopathy Induced by Manganese in Cell and Animal Models.

The molecular mechanism of Alzheimer-like cognitive impairment induced by manganese (Mn) exposure has not yet been fully clarified, and there are currently no effective interventions to treat neurodegenerative lesions related to manganism. Protein phosphatase 2 A (PP2A) is a major tau phosphatase and was recently identified as a potential therapeutic target molecule for neurodegenerative diseases; its activity is directed by the methylation status of the catalytic C subunit. Methionine is an essential amino acid, and its downstream metabolite S-adenosylmethionine (SAM) participates in transmethylation pathways as a methyl donor. In this study, the neurotoxic mechanism of Mn and the protective effect of methionine were evaluated in Mn-exposed cell and rat models. We show that Mn-induced neurotoxicity is characterized by PP2Ac demethylation accompanied by abnormally decreased LCMT-1 and increased PME-1, which are associated with tau hyperphosphorylation and spatial learning and memory deficits, and that the poor availability of SAM in the hippocampus is likely to determine the loss of PP2Ac methylation. Importantly, maintenance of local SAM levels through continuous supplementation with exogenous methionine, or through specific inhibition of PP2Ac demethylation by ABL127 administration in vitro, can effectively prevent tau hyperphosphorylation to reduce cellular oxidative stress, apoptosis, damage to cell viability, and rat memory deficits in cell or animal Mn exposure models. In conclusion, our data suggest that SAM and PP2Ac methylation may be novel targets for the treatment of Mn poisoning and neurotoxic mechanism-related tauopathies.