SciFed Journal of Immunology

How Metabolic Pathway get Involved in the Pathogenesis of SLE

SciFed Journal of Immunology

How Metabolic Pathway get Involved in the Pathogenesis of SLE


Received on: May 8, 2017, Accepted on: May 8, 2017, Published on: May 18, 2017

Citation: Hui-Hua Ding (2017) How Metabolic Pathway get Involved in the Pathogenesis of SLE. SF J Immunol 1:1.

Copyright: ©2017 Hui-Hua Ding. This is an open-access article disributed under the terms of the Creative Commons Attribution License, which permits unresricted use, disribution, and reproduction in any medium, provided the original author and source are credited.

  • Author

    Hui-Hua Ding

    Shanghai Jiao Tong University School of Medicine



           Systemic lupus erythematosus (SLE) is a systemic autoimmune disease characterized by a highly variable and unpredictable disease course as well as prognosis. It affects predominantly women of childbirth age, impacts their quality of life and brings huge economic burdens [1]. Due to earlier diagnosis and improved management of the disease, survival has greatly improved in the past decade [2]. Despite the significant improvement in mortality, the underlying pathogenic mechanisms remains to be elucidated. With the advent of new technologies, metabolomics studies have attribute to understanding the pathogenic mechanisms in SLE [3]. Although these studies mainly focused on exploring the metabolites profiling in SLE patients [4, 5, 67], the discoveries might link metabolic pathway to pathogenic mechanism and expand our knowledge in the pathogenesis of SLE. In other words, the disturbed metabolites profiling might yield clues to the underlying pathogenic mechanisms of SLE. Recently, Simanta and colleagues’ work have given a good illustration on how a key player in a metabolic pathway contributes to the development of SLE. In Simanta and colleagues study, they have revealed fatty acid amide hydrolase (FAAH), a primary hydrolytic enzyme for endogenous lipids, as a novel player in the pathogenesis of SLE [8].
          FAAH is a membrane bound serine hydrolase which is the principal catabolic enzyme for endogenous bioactive fatty acids [9]. The primary substrates of FAAH include anandamide (AEA), oleoyl ethanolamide and palmitoyl ethanolamide and their effects are mediated by cannabinoid receptors (CB1 and CB2) and peroxisome proliferator-activated receptors (PPARs) [9,10]. Both genetic deletion and pharmacological inhibition of FAAH displayed analgesia, anxiolysis and anti-depression effects in mice [10, 11, 1213]. While most studies focused on the therapeutic target of FAAH in central nervous system, other studies also demonstrate the anti-inflammation effects of FAAH inhibition, indicating the role of FAAH in autoimmune diseases. In experimental autoimmune encephalitis (EAE), blockade of FAAH in mice resulted in a less severe disease and improved long term outcome which might be mediated by its anti-inflammation and neuroprotective effects [14,15]. In inflammatory bowel disease (IBD) animal model, FAAH-defcient mice showed significant protection against drug induced colon inflammation [16]. Similarly, FAAH inhibitor reduced carrageenan-induced hind paw inflammation in mice [17]. More interestingly, plasmacytoid dendritic cells in multiple sclerosis patients expressed higher levels of FAAH [18] and FAAH expression was increased in patients’ astrocytes [19].However, the pathogenesis role of FAAH in SLE has not been revealed. The work by Simanta and colleagues for the first time demonstrated how FAAH got involved in the pathogenesis of SLE by using a transgenic mouse model [8].
          Congenic dissection studies have revealed Sle1, Sle2, and Sle3 as three major lupus susceptibility loci in the lupus murine model NZM2410 [20]. Sle2locus on chromosome 4 breaches B cell tolerance, promotes B cell hyperactivity and B1 cell expansion [21, 22]. While Sle2 locus was proved to contain several subintervals [21], the exact gene within this locus that impacts B cell tolerance remains unknown. Peripherally, B cell receptor (BCR) revision acts as an important mechanism for regulating self-reactive B cells during an ongoing immune response [23]. Simanta and colleagues used subcongenic recombinant mice to progressively narrowSle2 interval and found FAAH, a gene within Sle2locus, contributes to autoimmunity through heightened BCR revision in B cells [8]. By breedingB6.Sle2 mice onto hen egg lysozyme (HEL) BCR transgenic mice, they frst proved that Sle2was responsible for enhanced BCR revision, leading to the emergence of serum auto antibodies. Next, they identifed a telomeric subinterval (D4MIT331-D4MIT12) of the Sle2 interval responsible for enhanced BCR revision and recognized FAAH as the candidate responsible gene within the subinterval. Finally, in order to justify the hypothesis that FAAH was the responsible gene, FAAH gene expression and FAAH enzyme activity were measured and FAAH inhibitor was used. Strikingly, they found inhibition of FAAH reversed enhanced BCR revision by regulation of RAG expression, resulting in a signifcant decrease in serum autoantibody levels. Their fndings indicate that FAAH might be a promising therapeutic target in the treatment of lupus.
          FAAH inhibitorswere frst developed to increase the concentration of endocannabinoids. In the past few years, it has become an attractive therapeutic approach inconditions which could beneft from elevated levels of endocannabinoid. These conditions include neuropath ic pain, depression, anxiety disorders, Parkinson disease, multiple sclerosis, colitis, and cancer [24, 2526]. The beneft of FAAH inhibitor in the above conditions exclusively depends on the endocannabinoid system. In the lupus model studied by Simanta and colleagues, this beneft seems to be independent of the endocannabinoid system. Instead, it was related to the ability of FAAH inhibitor to reverse the enhanced BCR revision and polyreactivity in mature B cells. The fndings in this study have revealed a novel mechanism involved in FAAH inhibitory therapy. Further preclinical and clinical studies are warranted to evaluate the efcacy of FAAH inhibitor in reduce autoimmunity.
          On the other hand, the endocannabinoid system has not been widely studied in SLE. CB2 receptors and ligands are found primarily in immune cells, with B cells have the most abundant receptors [27]. A Polymorphism study suggest CB2 gene variation was related to reduced endocannabinoids’ immunomodulatory response and may be a risk factor for autoimmunity [28]. Endocannabinoids have been shown to suppress immune functions through modulation of The cell development, inhibition of cytotoxic NK cells, and regulation chemotaxis and cytokine secretion [27]. These evidences lead to an important question: whether FAAH inhibitor treatment functioned through the endocannabinoid system in the Sle2 congenic mice? It is rational to believe that FAAH inhibitor increased endocannabinoid level and in turn activate the CB2 receptor. Activation of CB2 further regulates the immune system through various mechanism. However, this was not further explored in Simanta and colleagues work, which warrants further study.
            In summary, the recent study by Simanta et al. provide several novel perspectives on the role of FAAH in the pathogenesis of SLE. For the frst time, FAAH was revealed to regulate receptor revision in mature B cell. Being a key enzyme in the metabolic pathway of endocannabinoids, the story of FAAH offers a good example on how metabolic pathway get involved in the pathogenesis of diseases. Furthermore, FAAH inhibitor might be a novel therapeutic target in SLE.


  1. Yazdany J, Yelin E (2010) Health-Related Quality of Life and Employment Among Persons with Systemic Lupus Erythematosus. Rheum Dis Clin North Am 36: 15-32.
  2. Bongu A, Chang E, Ramsey-Goldman R (2002) Can morbidity and mortality of SLE be improved? Best Pract Res Clin Rheumatol 16: 313-332.
  3. Ding H, Mohan C (2016) Connective tissue diseases: Promises and challenges of metabolomics in SLE. Nat Rev Rheumatol 12: 627-628.
  4. Ouyang X, Dai Y, Wen J, et al. (2011) 1H NMR-based metabolomic study of metabolic profling for systemic lupus erythematosus. Lupus 20: 1411-1420.
  5. Wu T, Xie C, Han J, et al. (2012) Metabolic disturbances associated with systemic lupus erythematosus. PLoS One 7: e37210.
  6. Saegusa J, Irino Y, Yoshida M, et al. (2014) GC/MS-based metabolomics detects metabolic alterations in serum from SLE patients. Clin Exp Rheumatol 32: 148.
  7. Bengtsson AA, Trygg J, Wuttge DM, et al. (2016) Metabolic Profling of Systemic Lupus Erythematosus and Comparison with Primary Sjogren’s Syndrome and Systemic Sclerosis. Kim KH ed PLoS One 11: e0159384.
  8. Pathak S, Kumar KR, Kanta H, et al. (2016) Fatty Acid Amide Hydrolase Regulates Peripheral B Cell Receptor Revision, Polyreactivity, and B1 Cells in Lupus. J Immunol 196: 1507-1516.
  9. Patricelli MP, Cravatt BF (1999) Fatty Acid Amide Hydrolase Competitively Degrades Bioactive Amides and Esters through a Nonconventional Catalytic Mechanism. Biochemistry 38:14125-14130.
  10. Cravatt BF, Demarest K, Patricelli MP, et al. (2001) Supersensitivity to anandamide and enhanced endogenous cannabinoid signaling in mice lacking fatty acid amide hydrolase. Proc Natl Acad Sci 98: 9371-9376.
  11. Lichtman AH, Shelton CC, Advani T, et al. (2004) Mice lacking fatty acid amide hydrolase exhibit a cannabinoid receptor-mediated phenotypic hypoalgesia. Pain 109: 319-327.
  12. Naidu PS, Varvel SA, Ahn K, Cravatt BF, et al. (2007) Evaluation of fatty acid amide hydrolase inhibition in murine models of emotionality. Psychopharmacology (Berl) 192: 61-70.
  13. Ahn K, Johnson DS, Cravatt BF (2009) Fatty acid amide hydrolase as a potential therapeutic target for the treatment of pain and CNS disorders. Expert Opin Drug Discov 4: 763-784.
  14. Rossi S, Furlan R, De Chiara V, et al. (2011) Cannabinoid CB1 receptors regulate neuronal TNF-α effects in experimental autoimmune encephalomyelitis. Brain Behav Immun 25: 1242-1248.
  15. Webb M, Luo L, Ma JY (2008) Genetic deletion of Fatty Acid Amide Hydrolase results in improved long-term outcome in chronic autoimmune encephalitis. Neurosci Lett 439: 106-110.
  16. Massa F, Marsicano G, Hermann H, et al. (2004) The endogenous cannabinoid system protects against colonic inflammation. J Clin Invest 113: 1202-1209.
  17. Holt S, Comelli F, Costa B, et al. (2005) Inhibitors of fatty acid amide hydrolase reduce carrageenan-induced hind paw inflammation in pentobarbital-treated mice: comparison with indomethacin and possible involvement of cannabinoid receptors. Br J Pharmacol 146: 467-476.
  18. Chiurchiu V, Cencioni MT, Bisicchia E, et al. (2013) Distinct modulation of human myeloid and plasmacytoid dendritic cells by anandamide in multiple sclerosis. Ann Neurol 73: 626-636.
  19. Benito C, Romero JP, Tolón RM, et al. (2007) Cannabinoid CB1 and CB2 receptors and fatty acid amide hydrolase are specifc markers of plaque cell subtypes in human multiple sclerosis. J Neurosci 27: 2396-2402.
  20. Morel L, Rudofsky UH, Longmate JA, et al. (1994) Polygenic control of susceptibility to murine systemic lupus erythematosus. Immunity 1: 219-229.
  21. Xu Z, Duan B, Croker BP, et al. (2005) Genetic Dissection of the Murine Lupus Susceptibility Locus Sle2: Contributions to Increased Peritoneal B-1a Cells and Lupus Nephritis Map to Different Loci. J Immunol 175: 936-943.
  22. Liu Y, Li L, Kumar KR, et al. (2007) Lupus Susceptibility Genes May Breach Tolerance to DNA by Impairing Receptor Editing of Nuclear Antigen-Reactive B Cells. J Immunol 179:1340-1352.
  23. Wang Y-H, Diamond B (2008) B cell receptor revision diminishes the autoreactive B cell response after antigen activation in mice. J Clin Invest 118: 2896-2907.
  24. Malftano AM, Ciaglia E, Gangemi G, et al. (2011) Update on the endocannabinoid system as an anticancer target. Expert Opin Ther Targets 15: 297-308.
  25. Pertwee RG (2014) Elevating endocannabinoid levels: pharmacological strategies and potential therapeutic applications. Proc Nutr Soc 73: 96-105.
  26. Petrosino S, Di Marzo V (2010) FAAH and MAGL inhibitors: therapeutic opportunities from regulating endocannabinoid levels. Curr Opin Investig Drugs 11: 51-62.
  27. Klein TW (2003) The cannabinoid system and immune modulation. J Leukoc Biol 74: 486-496.
  28. Sipe JC, Arbour N, Gerber A, et al. (2005) Reduced endocannabinoid immune modulation by a common cannabinoid 2 (CB2) receptor gene polymorphism: possible risk for autoimmune disorders. J Leukoc Biol 78: 231-238.