bims-imicid Biomed News
on Immunometabolism of infection, cancer and immune-mediated disease
Issue of 2021‒12‒26
eighteen papers selected by
Dylan Ryan
University of Cambridge

  1. J Biol Chem. 2021 Dec 17. pii: S0021-9258(21)01311-9. [Epub ahead of print] 101501
      Activated macrophages undergo metabolic reprogramming which not only supports their energetic demands but also allows for the production of specific metabolites that function as signalling molecules. Several Krebs cycle, or Krebs cycle-derived metabolites, including succinate, α-ketoglutarate and itaconate, have recently been shown to modulate macrophage function. The accumulation of 2-hydroxyglutarate (2HG) has also been well documented in transformed cells, and more recently shown to play a role in T cell and dendritic cell function. Here we have found that the abundance of both enantiomers of 2HG are increased in LPS-activated macrophages. We show that L-2HG, but not D-2HG, can promote the expression of the proinflammatory cytokine IL-1β and the adoption of an inflammatory, highly glycolytic metabolic state. These changes are likely mediated through activation of the transcription factor hypoxia inducible factor-1α (HIF-1α) by L-2HG, a known inhibitor of the HIF prolyl hydroxylases. Expression of the enzyme responsible for L-2HG degradation, L-2HG dehydrogenase (L-2HGDH), was also found to be decreased in LPS-stimulated macrophages and may therefore also contribute to L-2HG accumulation. Finally, over-expression of L-2HGDH in HEK293 TLR4/MD2/CD14 cells inhibited HIF-1α activation by LPS, whilst knockdown of L-2HGDH in macrophages boosted the induction of HIF-1α-dependent genes, as well as increasing LPS-induced HIF-1α activity. Taken together, this study therefore identifies L-2HG as a metabolite that can regulate HIF-1α in macrophages.
    Keywords:  L-2-hydroxyglutarate; glycolysis; hypoxia‐inducible factor (HIF); immunometabolism; inflammation; interleukin 1β (IL‐1β); macrophage
  2. Elife. 2021 Dec 24. pii: e71946. [Epub ahead of print]10
      Successful control of Mycobacterium tuberculosis (Mtb) infection by macrophages relies on immunometabolic reprogramming, where the role of fatty acids (FAs) remains poorly understood. Recent studies unraveled Mtb's capacity to acquire saturated and monounsaturated FAs via the Mce1 importer. However upon activation, macrophages produce polyunsaturated FAs (PUFAs), mammal-specific FAs mediating the generation of immunomodulatory eicosanoids. Here, we asked how Mtb modulates de novo synthesis of PUFAs in primary mouse macrophages and whether this benefits host or pathogen. Quantitative lipidomics revealed that Mtb infection selectively activates the biosynthesis of w6 PUFAs upstream of the eicosanoid precursor arachidonic acid (AA), via transcriptional activation of Fads2. Inhibiting FADS2 in infected macrophages impaired their inflammatory and antimicrobial responses but had no effect on Mtb growth in mice. Using a click-chemistry approach, we found that Mtb efficiently imports w6 PUFAs via Mce1 in axenic culture, including AA. Further, Mtb preferentially internalized AA over all other FAs within infected macrophages, by mechanisms partially depending on Mce1 and supporting intracellular persistence. Notably, IFNγ repressed de novo synthesis of AA by infected mouse macrophages and restricted AA import by intracellular Mtb. Together, these findings identify AA as a major FA substrate for intracellular Mtb, whose mobilization by innate immune responses is opportunistically hijacked by the pathogen and downregulated by IFNγ.
    Keywords:  immunology; infectious disease; inflammation; microbiology; mouse
  3. Antioxidants (Basel). 2021 Dec 06. pii: 1954. [Epub ahead of print]10(12):
      The run/cysteine-rich-domain-containing Beclin1-interacting autophagy protein (Rubicon) is essential for the regulation of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase by interacting with p22phox to trigger the production of reactive oxygen species (ROS) in immune cells. In a previous study, we demonstrated that the interaction of Rubicon with p22phox increases cellular ROS levels. The correlation between Rubicon and mitochondrial ROS (mtROS) is poorly understood. Here, we report that Rubicon interacts with p22phox in the outer mitochondrial membrane in macrophages and patients with human ulcerative colitis. Upon lipopolysaccharide (LPS) activation, the binding of Rubicon to p22phox was elevated, and increased not only cellular ROS levels but also mtROS, with an impairment of mitochondrial complex III and mitochondrial biogenesis in macrophages. Furthermore, increased Rubicon decreases mitochondrial metabolic flux in macrophages. Mito-TIPTP, which is a p22phox inhibitor containing a mitochondrial translocation signal, enhances mitochondrial function by inhibiting the association between Rubicon and p22phox in LPS-primed bone-marrow-derived macrophages (BMDMs) treated with adenosine triphosphate (ATP) or dextran sulfate sodium (DSS). Remarkably, Mito-TIPTP exhibited a therapeutic effect by decreasing mtROS in DSS-induced acute or chronic colitis mouse models. Thus, our findings suggest that Mito-TIPTP is a potential therapeutic agent for colitis by inhibiting the interaction between Rubicon and p22phox to recover mitochondrial function.
    Keywords:  Rubicon; colitis; mitochondria; p22phox; reactive oxygen species
  4. Redox Biol. 2021 Dec 18. pii: S2213-2317(21)00377-3. [Epub ahead of print]49 102217
      Maintaining host iron homeostasis is an essential component of nutritional immunity responsible for sequestrating iron from pathogens and controlling infection. Nucleotide-oligomerization domain-like receptors (NLRs) contribute to cytoplasmic sensing and antimicrobial response orchestration. However, it remains unknown whether and how NLRs may regulate host iron metabolism, an important component of nutritional immunity. Here, we demonstrated that NLRP6, a member of the NLR family, has an unconventional role in regulating host iron metabolism that perturbs host resistance to bacterial infection. NLRP6 deficiency is advantageous for maintaining cellular iron homeostasis in both macrophages and enterocytes through increasing the unique iron exporter ferroportin-mediated iron efflux in a nuclear factor erythroid-derived 2-related factor 2 (NRF2)-dependent manner. Additional studies uncovered a novel mechanism underlying NRF2 regulation and operating through NLRP6/AKT interaction and that causes a decrease in AKT phosphorylation, which in turn reduces NRF2 nuclear translocation. In the absence of NLRP6, increased AKT activation promotes NRF2/KEAP1 dissociation via increasing mTOR-mediated p62 phosphorylation and downregulates KEAP1 transcription by promoting FOXO3A phosphorylation. Together, our observations provide new insights into the mechanism of nutritional immunity by revealing a novel function of NLRP6 in regulating iron metabolism, and suggest NLRP6 as a therapeutic target for limiting bacterial iron acquisition.
    Keywords:  Ferroportin; Iron metabolism; NLRP6; Nutritional immunity; Salmonella Typhimurium
  5. Cell Mol Gastroenterol Hepatol. 2021 Dec 21. pii: S2352-345X(21)00260-5. [Epub ahead of print]
      BACKGROUND & AIMS: Inflammation is the hallmark of chronic liver disease. Metabolism is a key determinant to regulate the activation of immune cells. Here we define the role of Sirtuin1 (SIRT1), a main metabolic regulator, in controlling the activation of macrophages during cholestatic liver disease and in response to endotoxin.METHODS: We have used mice overexpressing SIRT1 which we treated with intraperitoneal LPS or induced cholestasis by the ligation of the bile duct (BDL). Bone Marrow Derived Macrophages were used for mechanistic in vitro studies. Finally, PEPC-Boy mice were used for adoptive transfer experiments to elucidate the impact of SIRT1 overexpressing macrophages in contributing to cholestatic liver disease.
    RESULTS: We found that SIRT1 overexpression promotes increased liver inflammation and liver injury after LPS/GalN and BDL; this was associated with an increased activation of the inflammasome in macrophages. Mechanistically, SIRT1 overexpression associated with the activation of the mTOR pathway that led to increased activation of macrophages, which showed metabolic rewiring with increased glycolysis and broken TCA cycle in response to endotoxin in vitro. Activation of the SIRT1/mTOR axis in macrophages associated with the activation of the inflammasome and the attenuation of autophagy. Ultimately, in an in vivo model of cholestatic disease, the transplantation of SIRT1 overexpressing myeloid cells contributed to liver injury and fibrosis.
    CONCLUSIONS: Our study provides novel mechanistic insights into the regulation of macrophages during cholestatic disease and the response to endotoxin, where the SIRT1/mTOR crosstalk regulates macrophage activation controlling the inflammasome, autophagy and metabolic rewiring.
    Keywords:  SIRT1; cholestasis; inflammasome; macrophages; metabolism
  6. Int J Mol Sci. 2021 Dec 20. pii: 13668. [Epub ahead of print]22(24):
      The capacity of T cells to identify and kill cancer cells has become a central pillar of immune-based cancer therapies. However, T cells are characterized by a dysfunctional state in most tumours. A major obstacle for proper T-cell function is the metabolic constraints posed by the tumour microenvironment (TME). In the TME, T cells compete with cancer cells for macronutrients (sugar, proteins, and lipid) and micronutrients (vitamins and minerals/ions). While the role of macronutrients in T-cell activation and function is well characterized, the contribution of micronutrients and especially ions in anti-tumour T-cell activities is still under investigation. Notably, ions are important for most of the signalling pathways regulating T-cell anti-tumour function. In this review, we discuss the role of six biologically relevant ions in T-cell function and in anti-tumour immunity, elucidating potential strategies to adopt to improve immunotherapy via modulation of ion metabolism.
    Keywords:  T cell; immunomodulation; ions; nutrient competition; tumour microenvironment
  7. J Pharmacol Sci. 2022 Jan;pii: S1347-8613(21)00092-X. [Epub ahead of print]148(1): 31-40
      Ingestion of amino acids is fundamental for cellular activity. Amino acids are important components for protein synthesis but are also crucial for intracellular metabolic reactions and signal transduction. Following activation, immune cells induce metabolic reprogramming to generate adequate energy and constitutive substances. Hence, the delivery of amino acids by transporters is necessary for the progression of metabolic rewiring. In this review, we discuss how amino acids and their transporters regulate immune cell functions, with emphasis on LAT1, a transporter of large neutral amino acids. Furthermore, we explore the possibility of targeting amino acid transporters to improve immune disorders and cancer immune therapies.
    Keywords:  Amino acid transporter; Cancer immunotherapy; Inflammatory disease; LAT1; T cell
  8. Front Immunol. 2021 ;12 790658
      Over the last decades, the frequency of allergic disorders has steadily increased. Immunologically, allergies are caused by abnormal immune responses directed against otherwise harmless antigens derived from our environment. Two of the main cell types driving allergic sensitization and inflammation are IgE-producing plasma cells and Th2 cells. The acute activation of T and B cells, their differentiation into effector cells, as well as the formation of immunological memory are paralleled by distinct changes in cellular metabolism. Understanding the functional consequences of these metabolic changes is the focus of a new research field termed "immune metabolism". Currently, the contribution of metabolic changes in T and B cells to either the development or maintenance of allergies is not completely understood. Therefore, this mini review will introduce the fundamentals of energy metabolism, its connection to immune metabolism, and subsequently focus on the metabolic phenotypes of IL-4-activated B cells and Th2 cells.
    Keywords:  Warburg metabolism; allergies; fatty acid oxidation (FAO); glycolysis; immune metabolism; metabolism; oxidative phosphorylation
  9. Front Immunol. 2021 ;12 722320
      The inhibition of anabolic pathways, such as aerobic glycolysis, is a metabolic cornerstone of memory T cell differentiation and function. However, the signals that hamper these anabolic pathways are not completely known. Recent evidence pinpoints the chemokine receptor CCR5 as an important player in CD4+ T cell memory responses by regulating T cell antigen receptor (TCR) nanoclustering in an antigen-independent manner. This paper reports that CCR5 specifically restrains aerobic glycolysis in memory-like CD4+ T cells, but not in effector CD4+ T cells. CCR5-deficient memory CD4+ T cells thus show an abnormally high glycolytic/oxidative metabolism ratio. No CCR5-dependent change in glucose uptake nor in the expression of the main glucose transporters was detected in any of the examined cell types, although CCR5-deficient memory cells did show increased expression of the hexokinase 2 and pyruvate kinase M2 isoforms, plus the concomitant downregulation of Bcl-6, a transcriptional repressor of these key glycolytic enzymes. Further, the TCR nanoclustering defects observed in CCR5-deficient antigen-experienced CD4+ T cells were partially reversed by incubation with 2-deoxyglucose (2-DG), suggesting a link between inhibition of the glycolytic pathway and TCR nanoscopic organization. Indeed, the treatment of CCR5-deficient lymphoblasts with 2-DG enhanced IL-2 production after antigen re-stimulation. These results identify CCR5 as an important regulator of the metabolic fitness of memory CD4+ T cells, and reveal an unexpected link between T cell metabolism and TCR organization with potential influence on the response of memory T cells upon antigen re-encounter.
    Keywords:  BCL6; CCR5; chemokine signaling; efector CD4+ T cells; glycolysis; memory CD4+ T cells; metabolic reprogramming
  10. Prostaglandins Other Lipid Mediat. 2021 Dec 15. pii: S1098-8823(21)00079-4. [Epub ahead of print]158 106604
      Adipose tissue contains a complex immune environment and is a central contributor to heightened systemic inflammation in obese persons. Epoxyeicosatrienoic acids (EETs) are lipid signaling molecules that decrease inflammation in obese animals, but their effect on inflammation in humans is unknown. The enzyme soluble epoxide hydrolase (sEH) hydrolyzes EETs to less active diols, and we hypothesized that pharmacologic sEH inhibition would decrease adipose inflammation in obese individuals. We treated obese prediabetic adults with the sEH inhibitor GSK2256294 versus placebo in a crossover design, collected subcutaneous abdominal adipose tissue via lipoaspiration and characterized the tissue T cell profile. Treatment with GSK2256294 decreased the percentage of pro-inflammatory T cells producing interferon-gamma (IFNγ), but not interleukin (IL)-17A, and decreased the amount of secreted tumor necrosis factor-alpha (TNFα). Understanding the contribution of the EET/sEH pathway to inflammation in obesity could lead to new strategies to modulate adipose and systemic inflammation.
    Keywords:  Adipose; Epoxyeicosatrienoic acids; Inflammation; Obesity; Soluble epoxide hydrolase
  11. Biochem Biophys Res Commun. 2021 Dec 17. pii: S0006-291X(21)01685-5. [Epub ahead of print]588 34-40
      Glucocorticoids (GCs), immunosuppressive, and anti-inflammatory agents have various effects on T cells. However, the long-term influence of GCs on the T cell-mediated immune response remain to be elucidated. We demonstrated that the administration of GC during the TCR-mediated activation phase induced long-lasting suppression of glycolysis, even after the withdrawal of GC. The acquisition of the effector functions was inhibited, while the expression of PD-1 was increased in CD8 T cells activated in the presence of GC. Furthermore, adoptive transfer experiments revealed that GC-treated CD8 T cells reduced memory T cell formation and anti-tumor activity. These findings reveal that GCs have long-lasting influence on the T cell-mediated immune response via modulation of T cell metabolism.
    Keywords:  CD8 T cells; Glucocorticoid; Glycolysis; Memory T cells; Programed cell death 1; Tumor immunity
  12. Nat Immunol. 2021 Dec 23.
      Antigen-specific memory CD4+ T cells can persist and confer rapid and efficient protection from microbial reinfection. However, the mechanisms underlying the long-term maintenance of the memory CD4+ T cell pool remain largely unknown. Here, using a mouse model of acute infection with lymphocytic choriomeningitis virus (LCMV), we found that the serine/threonine kinase complex mammalian target of rapamycin complex 2 (mTORC2) is critical for the long-term persistence of virus-specific memory CD4+ T cells. The perturbation of mTORC2 signaling at memory phase led to an enormous loss of virus-specific memory CD4+ T cells by a unique form of regulated cell death (RCD), ferroptosis. Mechanistically, mTORC2 inactivation resulted in the impaired phosphorylation of downstream AKT and GSK3β kinases, which induced aberrant mitochondrial reactive oxygen species (ROS) accumulation and ensuing ferroptosis-causative lipid peroxidation in virus-specific memory CD4+ T cells; furthermore, the disruption of this signaling cascade also inhibited glutathione peroxidase 4 (GPX4), a major scavenger of lipid peroxidation. Thus, the mTORC2-AKT-GSK3β axis functions as a key signaling hub to promote the longevity of virus-specific memory CD4+ T cells by preventing ferroptosis.
  13. Front Immunol. 2021 ;12 733808
      Accumulating evidence reveals that both inflammation and lymphocyte dysfunction play a vital role in the development of diabetic nephropathy (DN). Hyperoside (HPS) or quercetin-3-O-galactoside is an active flavonoid glycoside mainly found in the Chinese herbal medicine Tu-Si-Zi. Although HPS has a variety of pharmacological effects, including anti-oxidative and anti-apoptotic activities as well as podocyte-protective effects, its underlying anti-inflammatory mechanisms remain unclear. Herein, we investigated the therapeutic effects of HPS on murine DN and the potential mechanisms responsible for its efficacy. We used C57BLKS/6J Lep db/db mice and a high glucose (HG)-induced bone marrow-derived macrophage (BMDM) polarization system to investigate the potentially protective effects of HPS on DN. Our results showed that HPS markedly reduced diabetes-induced albuminuria and glomerular mesangial matrix expansion, accompanied with a significant improvement of fasting blood glucose level, hyperlipidaemia and body weight. Mechanistically, pretreatment with HPS effectively regulated macrophage polarization by shifting proinflammatory M1 macrophages (F4/80+CD11b+CD86+) to anti-inflammatory M2 ones (F4/80+CD11b+CD206+) in vivo and in bone marrow-derived macrophages (BMDMs) in vitro, resulting in the inhibition of renal proinflammatory macrophage infiltration and the reduction in expression of monocyte chemoattractant protein-1 (MCP-1), tumor necrosis factor (TNF-α) and inducible nitric oxide synthase (iNOS) while increasing expression of anti-inflammatory cytokine Arg-1 and CD163/CD206 surface molecules. Unexpectedly, pretreatment with HPS suppressed CD4+ T cell proliferation in a coculture model of IL-4-induced M2 macrophages and splenic CD4+ T cells while promoting their differentiation into CD4+IL-4+ Th2 and CD4+Foxp3+ Treg cells. Taken together, we demonstrate that HPS ameliorates murine DN via promoting macrophage polarization from an M1 to M2 phenotype and CD4+ T cell differentiation into Th2 and Treg populations. Our findings may be implicated for the treatment of DN in clinic.
    Keywords:  Th1 cell; Treg cell; diabetic nephropathy; hyperoside; macrophage polarization; renal inflammation
  14. Cell Immunol. 2021 Dec 17. pii: S0008-8749(21)00189-1. [Epub ahead of print]371 104470
      Inflammatory responses are required to block pathogen infection but can also lead to hypersensitivity and chronic inflammation. Barrier tissues actively release IL-33, ATP, and other alarmins during cell stress, helping identify pathogenic stimuli. However, it is unclear how these signals are integrated. Mast cells are critical initiators of allergic inflammation and respond to IL-33 and ATP. We found that mouse mast cells had a 3-6-fold increase in ATP-induced cytokine production when pre-treated with IL-33. This effect was observed at ATP concentrations < 100 µM and required < 30-minute IL-33 exposure. ATP-induced degranulation was not enhanced by pretreatment nor was the response to several pathogen molecules. Mechanistic studies implicated the P2X7 receptor and calcineurin/NFAT pathway in the enhanced ATP response. Finally, we found that IL-33 + ATP co-stimulation enhanced peritoneal eosinophil and macrophage recruitment. These results support the hypothesis that alarmins collaborate to surpass a threshold necessary to initiate an inflammatory response.
    Keywords:  ATP; Alarmin; IL-33; Inflammation; Mast cell; P2X7; Peritonitis
  15. Cells. 2021 Dec 09. pii: 3480. [Epub ahead of print]10(12):
      Obesity is associated with chronic low-grade inflammation. The benefits of exercise are partly attributed to its anti-inflammatory effect, but whether exercise can regulate NLRP3 inflammasome activation in obese adipose tissue remains unknown. Meteorin-like (METRNL), a recently discovered myokine, has been implicated in mediating the effect of exercise on metabolism. Herein, we examined the effect of exercise and METRNL on NLRP3 inflammasome activation. High-fat diet (HFD)-induced obese mice were subjected to treadmill exercise for 8 weeks. A subgroup of HFD mice was switched to normal chow with the exercise intervention. Exercise and diet attenuated weight gain, fat accumulation, and insulin resistance in obese mice. In addition, exercise downregulated gene and protein levels of inflammasome markers, including NLRP3 and caspase-1, in adipose tissue. In isolated bone marrow-derived macrophages, activation of NLRP3 inflammasome was suppressed in the exercise group, as confirmed by the downregulation of IL-1β and IL-18. Exercise significantly enhanced the expression of METRNL in various muscle depots, and further in vitro analysis revealed that recombinant METRNL treatment inhibited IL-1β secretion in macrophages. In conclusion, exercise exerts its anti-inflammatory action by suppressing adipose tissue NLRP3 inflammasome, and this is, in part, associated with METRNL induction in muscle and its anti-inflammatory effects in macrophages.
    Keywords:  METRNL; NLRP3 inflammasome; adipose tissue; exercise; myokines; type 2 diabetes
  16. Nat Metab. 2021 Dec;3(12): 1596-1607
      Non-alcoholic fatty liver disease (NAFLD) has emerged pandemically across the globe and particularly affects patients with obesity and type 2 diabetes. NAFLD is a complex systemic disease that is characterised by hepatic lipid accumulation, lipotoxicity, insulin resistance, gut dysbiosis and inflammation. In this review, we discuss how metabolic dysregulation, the gut microbiome, innate and adaptive immunity and their interplay contribute to NAFLD pathology. Lipotoxicity has been shown to instigate liver injury, inflammation and insulin resistance. Synchronous metabolic dysfunction, obesity and related nutritional perturbation may alter the gut microbiome, in turn fuelling hepatic and systemic inflammation by direct activation of innate and adaptive immune responses. We review evidence suggesting that, collectively, these unresolved exogenous and endogenous cues drive liver injury, culminating in liver fibrosis and advanced sequelae of this disorder such as liver cirrhosis and hepatocellular carcinoma. Understanding NAFLD as a complex interplay between metabolism, gut microbiota and the immune response will challenge the clinical perception of NAFLD and open new therapeutic avenues.
  17. Oxid Med Cell Longev. 2021 ;2021 5833857
      High-fat diet-induced fatty liver is an indolent and chronic disease accompanied by immune dysfunction and metabolic disturbances involving numerous biological pathways. This study investigated how this abnormal metabolic disorder influences sepsis in mice. Mice were fed with normal chow (NC) or high-fat diet (HFD), and palmitic acid (PA) was used to treat hepatocytes to mimic fat accumulation in vitro. Lipopolysaccharide (LPS) was used to induce sepsis and related immune responses. Mice fed on a high-fat diet displayed higher mortality and more severe liver damage but compromised immunoreaction. The supernatant from PA-treated primary hepatocytes markedly diminished the inflammatory cytokine expression of macrophages after LPS stimulation, which showed a state of immunosuppression. Metabolomics analysis indicated the level of many key metabolites with possible roles in immunoreaction was altered in the HFD and PA groups compared with corresponding controls; specifically, β-hydroxybutyric acid (BHB) showed an immunosuppressive effect on Raw264.7 cells during the LPS stimulation. Transcriptomic analysis suggested that several differential signaling pathways may be associated with the alteration of immune function between the NC and HFD groups, as well as in the in vitro model. Our study suggests that the consumption of HFD may alter the hepatic metabolic profile, and that certain metabolites may remold the immune system to immunosuppressive state in the context of sepsis.
  18. J Environ Pathol Toxicol Oncol. 2021 ;40(4): 43-52
      The disease progression of rheumatoid arthritis (RA) is closely related to the disorder of amino acids metabolism. This study aimed to clarify the changes in the categories, quantities and metabolic pathways of amino acids associated with disease progression in adjuvant-induced arthritis (AIA) rats, and to evaluate the application value of amino acids metabolic profiling in the diagnosis of RA. A total of 20 rats were randomized into a control group and AIA model group. Thirty-three days after modeling, the synovial tissues of left ankle joints were collected for histopathological examination. Also, untargeted metabolomics based on UPLC-LTQ/Orbitrap MS was used to identify the potential amino acids and analyze the changes of their metabolic pathways. Histopathological observation showed that the synovial tissues of AIA rats exhibited hyperplastic and inflammatory lesions. Through multivariate statistical analysis, a total of 12 amino acids were identified and considered to show metabolic changes in AIA rats. Compared with the control group, the concentrations of glutamate, arginine, methionine were increased in the AIA model group; while the concentrations of proline, valine, tyrosine, phenylalanine, leucine, glycine, tryptophan, histidine, threonine were decreased. Metabolic pathway analysis showed that the selected amino acids had important physiological functions in immune and inflammatory response. The results suggested that amino acids could be employed as biomarkers closely related to RA, and the analysis of amino acids metabolic profiling also exhibited potential application value in the diagnosis, disease progression monitoring and therapy of RA.