Cellular Recycling Gone Wrong: The Role of Dysregulated Autophagy and Hyperactive mTORC1 in the Pathogenesis of Sarcoidosis
Main Article Content
Keywords
autophagy, granulomatous disease, sarcoidosis, mTOR, treatment
Abstract
Background and aims: Autophagy is a highly regulated, complex intracellular recycling process that is vital to maintaining cellular homeostasis in response to diverse conditions and stressors. Despite the presence of robust regulatory pathways, the intricate and multi-step nature of autophagy creates opportunity for dysregulation. Errors in autophagy have been implicated in the development of a broad range of clinical pathologies including granulomatous disease. Specifically, activation of the mTORC1 pathway has been identified as a key negative regulator of autophagic flux, prompting the study of dysregulated mTORC1 signaling in the pathogenesis of sarcoidosis.
Our review: We conducted a thorough search of the extant literature to identify the regulatory pathways of autophagy, and more specifically the implication of upregulated mTORC1 pathways in the pathogenesis of sarcoidosis. We review data showing spontaneous granuloma formation in animal models with upregulate mTORC1 signaling, human genetic studies showing mutation in autophagy genes in sarcoidosis patients, and clinical data showing that targeting autophagy regulatory molecules like mTORC1 may provide new therapeutic approaches for sarcoidosis.
Conclusions: Given the incomplete understanding of sarcoidosis pathogenesis and the toxicities of current treatments, a more complete understanding of sarcoidosis pathogenesis is crucial for the development of more effective and safer therapies. In this review, we propose a strong molecular pathway driving sarcoidosis pathogenesis at which autophagy is at the center. A more complete understanding of autophagy and its regulatory molecules, like mTORC1, may provide a window into new therapeutic approaches for sarcoidosis.
Downloads
References
2. Perlman DM, Sudheendra MT, Furuya Y, et al. Clinical Presentation and Treatment of High-Risk Sarcoidosis. Ann Am Thorac Soc 2021;18(12):1935-1947. doi:10.1513/ANNALSATS.202102-212CME
3. Glick D, Barth S, Macleod KF. Autophagy: Cellular and molecular mechanisms. Journal of Pathology 2010;221(1):3-12. doi:10.1002/path.2697
4. Sarkar S. Regulation of autophagy by mTOR-dependent and mTOR-independent pathways: Autophagy dysfunction in neurodegenerative diseases and therapeutic application of autophagy enhancers. Biochem Soc Trans 2013;41(5):1103-1130. doi:10.1042/BST20130134
5. Behrends C, Sowa ME, Gygi SP, Harper JW. Network organization of the human autophagy system. Nature 2010;466(7302):68-76. doi:10.1038/nature09204
6. Shang L, Wang X. AMPK and mTOR coordinate the regulation of Ulk1 and mammalian autophagy initiation. Autophagy 2011;7(8):924-926. doi:10.4161/auto.7.8.15860
7. Martina JA, Chen Y, Gucek M, Puertollano R. MTORC1 functions as a transcriptional regulator of autophagy by preventing nuclear transport of TFEB. Autophagy 2012;8(6):903-914. doi:10.4161/AUTO.19653
8. Justice MJ, Bronova I, Schweitzer KS, et al. Inhibition of acid sphingomyelinase disrupts LYNUS signaling and triggers autophagy. J Lipid Res 2018;59(4):596-606. doi:10.1194/JLR.M080242
9. Mizushima N, Levine B. Autophagy in Human Diseases. N Engl J Med 2020;383(16):1564-1576. doi:10.1056/NEJMRA2022774
10. Newman LS, Rose CS, Bresnitz EA, et al. A case control etiologic study of sarcoidosis: environmental and occupational risk factors. Am J Respir Crit Care Med 2004;170(12):1324-1330. doi:10.1164/RCCM.200402-249OC
11. Brownell I, Ramiŕez-Valle F, Sanchez M, Prystowsky S. Evidence for mycobacteria in sarcoidosis. Am J Respir Cell Mol Biol 2011;45(5):899-905. doi:10.1165/RCMB.2010-0433TR
12. Rotsinger JE, Celada LJ, Polosukhin V v., Atkinson JB, Drake WP. Molecular Analysis of Sarcoidosis Granulomas Reveals Antimicrobial Targets. Am J Respir Cell Mol Biol 2016;55(1):128-134. doi:10.1165/RCMB.2015-0212OC
13. Ishige I, Usui Y, Takemura T, Eishi Y. Quantitative PCR of mycobacterial and propionibacterial DNA in lymph nodes of Japanese patients with sarcoidosis. Lancet 1999;354(9173):120-123. doi:10.1016/S0140-6736(98)12310-3
14. Swaisgood CM, Oswald-Richter K, Moeller SD, et al. Development of a sarcoidosis murine lung granuloma model using Mycobacterium superoxide dismutase A peptide. Am J Respir Cell Mol Biol 2011;44(2):166-174. doi:10.1165/RCMB.2009-0350OC
15. McCaskill JG, Chason KD, Hua X, et al. Pulmonary immune responses to Propionibacterium acnes in C57BL/6 and BALB/c mice. Am J Respir Cell Mol Biol 2006;35(3):347-356. doi:10.1165/RCMB.2005-0285OC
16. Fratti RA, Chua J, Vergne I, Deretic V. Mycobacterium tuberculosis glycosylated phosphatidylinositol causes phagosome maturation arrest. Proc Natl Acad Sci U S A 2003;100(9):5437-5442. doi:10.1073/pnas.0737613100
17. Gutierrez MG, Master SS, Singh SB, Taylor GA, Colombo MI, Deretic V. Autophagy is a defense mechanism inhibiting BCG and Mycobacterium tuberculosis survival in infected macrophages. Cell 2004;119(6):753-766. doi:10.1016/j.cell.2004.11.038
18. C L, H P, L J, et al. Inhibition of neutral sphingomyelinase protects mice against systemic tuberculosis. Front Biosci (Elite Ed) 2016;8(2):311-325. doi:10.2741/E769
19. Crouser ED, Locke LW, Julian MW, et al. Phagosome-regulated mTOR signalling during sarcoidosis granuloma biogenesis. Eur Respir J 2021;57(3). doi:10.1183/13993003.02695-2020
20. Linke M, Pham HTT, Katholnig K, et al. Chronic signaling via the metabolic checkpoint kinase mTORC1 induces macrophage granuloma formation and marks sarcoidosis progression. Nat Immunol 2017;18(3):293-302. doi:10.1038/ni.3655
21. Lockstone HE, Sanderson S, Kulakova N, et al. Gene set analysis of lung samples provides insight into pathogenesis of progressive, fibrotic pulmonary sarcoidosis. Am J Respir Crit Care Med 2010;181(12):1367-1375. doi:10.1164/rccm.200912-1855OC
22. Pizzini A, Bacher H, Aichner M, et al. High expression of mTOR signaling in granulomatous lesions is not predictive for the clinical course of sarcoidosis. Respir Med 2021;177(March 2020). doi:10.1016/j.rmed.2020.106294
23. Calender A, Lim CX, Weichhart T, et al. Exome sequencing and pathogenicitynetwork analysis of five French families implicate mTOR signalling and autophagy in familial sarcoidosis. European Respiratory Journal 2019;54(2):10-13. doi:10.1183/13993003.00430-2019
24. Cozier YC, Berman JS, Palmer JR, Boggs DA, Serlin DM, Rosenberg L. Sarcoidosis in black women in the United States: Data from the Black Women’s Health Study. Chest 2011;139(1):144-150. doi:10.1378/chest.10-0413
25. Dubé JJ, Collyer ML, Trant S, et al. Decreased mitochondrial dynamics is associated with insulin resistance, metabolic rate, and fitness in African Americans. Journal of Clinical Endocrinology and Metabolism 2020;105(4):1210-1220. doi:10.1210/clinem/dgz272
26. Murase D, Hachiya A, Takano K, et al. Autophagy has a significant role in determining skin color by regulating melanosome degradation in keratinocytes. Journal of Investigative Dermatology 2013;133(10):2416-2424. doi:10.1038/jid.2013.165
27. Rossides M, Grunewald J, Eklund A, et al. Familial aggregation and heritability of sarcoidosis: A Swedish nested case-control study. European Respiratory Journal 2018;52(2). doi:10.1183/13993003.00385-2018
28. Oliván S, Calvo AC, Manzano R, Zaragoza P, Osta R. Sex differences in constitutive autophagy. Biomed Res Int 2014;2014. doi:10.1155/2014/652817
29. Lista P, Straface E, Brunelleschi S, Franconi F, Malorni W. On the role of autophagy in human diseases: a gender perspective. J Cell Mol Med 2011;15(7):1443-1457. doi:10.1111/J.1582-4934.2011.01293.X
30. Shang D, Wang L, Klionsky DJ, Cheng H, Zhou R. Sex differences in autophagy-mediated diseases: toward precision medicine. Autophagy 2021;17(5):1065-1076. doi:10.1080/15548627.2020.1752511
31. de Vries J, van Heck GL, Drent M. Gender differences in sarcoidosis: symptoms, quality of life, and medical consumption. Women Health 1999;30(2):99-114. doi:10.1300/J013V30N02_07
32. Birnbaum AD, Rifkin LM. Sarcoidosis: sex-dependent variations in presentation and management. J Ophthalmol 2014;2014. doi:10.1155/2014/236905
33. Arkema E V., Cozier YC. Epidemiology of sarcoidosis: current findings and future directions. Ther Adv Chronic Dis 2018;9(11):227-240. doi:10.1177/2040622318790197
34. Wainaina Wambui D, Ndili Obi O, Dale Kearney G. Association Between Obesity and Sarcoidosis: A Systematic Review and Meta-analysis. American Journal of Internal Medicine 2020;8(5):237. doi:10.11648/j.ajim.20200805.18
35. Cozier YC, Govender P, Berman JS. Obesity and sarcoidosis: consequence or contributor? Curr Opin Pulm Med 2018;24(5):487-494. doi:10.1097/MCP.0000000000000503
36. Um SH, Frigerio F, Watanabe M, et al. Absence of S6K1 protects against age- and diet-induced obesity while enhancing insulin sensitivity. Nature 2004;431(7005):200-205. doi:10.1038/NATURE02866
37. Dann SG, Selvaraj A, Thomas G. mTOR Complex1-S6K1 signaling: at the crossroads of obesity, diabetes and cancer. Trends Mol Med 2007;13(6):252-259. doi:10.1016/J.MOLMED.2007.04.002
38. Namkoong S, Cho CS, Semple I, Lee JH. Autophagy Dysregulation and Obesity-Associated Pathologies. Mol Cells 2018;41(1):3-10. doi:10.14348/MOLCELLS.2018.2213
39. Obi ON, Lower EE, Baughman RP. Biologic and advanced immunomodulating therapeutic options for sarcoidosis: a clinical update. Expert Rev Clin Pharmacol 2021;14(2):179-210. doi:10.1080/17512433.2021.1878024
40. el Jammal T, Jamilloux Y, Gerfaud-Valentin M, Valeyre D, Sève P. Refractory sarcoidosis: A review. Ther Clin Risk Manag 2020;16:323-345. doi:10.2147/TCRM.S192922
41. Manzia TM, Bellini MI, Corona L, et al. Successful treatment of systemic de novo sarcoidosis with cyclosporine discontinuation and provision of rapamune after liver transplantation. Transplant International 2011;24(8):69-70. doi:10.1111/j.1432-2277.2011.01256.x
42. Gupta N, Bleesing JH, McCormack FX. Successful response to treatment with sirolimus in pulmonary sarcoidosis. Am J Respir Crit Care Med 2020;202(9):E119-E120. doi:10.1164/rccm.202004-0914IM
43. Nguyen QD, Ibrahim MA, Watters A, et al. Ocular tolerability and efficacy of intravitreal and subconjunctival injections of sirolimus in patients with non-infectious uveitis: Primary 6-month results of the SAVE Study. J Ophthalmic Inflamm Infect 2013;3(1):1-15. doi:10.1186/1869-5760-3-32
44. Ibrahim MA, Sepah YJ, Watters A, et al. One-Year Outcomes of the SAVE Study: S irolimus as a Therapeutic A pproach for U VE itis . Transl Vis Sci Technol 2015;4(2):4. doi:10.1167/tvst.4.2.4
45. Nguyen QD, Merrill PT, Clark WL, et al. Intravitreal Sirolimus for Noninfectious Uveitis: A Phase III Sirolimus Study Assessing Double-masKed Uveitis TReAtment (SAKURA). Ophthalmology 2016;123(11):2413-2423. doi:10.1016/j.ophtha.2016.07.029
46. Quan Dong Nguyen, MD, MSc, Mohammad Ali Sadiq, MD (by invitation), Mohamed Kamel Soliman, MD (by invitation), Aniruddha Agarwal, MD (by invitation), Diana V. Do, MD (by invitation), Yasir J. Sepah M (by invitation), ABSTRACT. The effect of different dosing schedules of intravitreal sirolimus, a mammalian target of rapamycin (mTOR) inhibitor in the treatment of non-infectious uveitis (an American Ophthalmological Society thesis). Trans Am Ophthalmol Soc 2016;114(T3):1-14.
47. Cabahug VLO, Uy HS, Yu-Keh E, Sapno KJD. Outcomes of treatment with sirolimus for non-infectious uveitis: A meta-analysis and systematic review. Clinical Ophthalmology 2019;13:649-669. doi:10.2147/OPTH.S198401
48. Chen ES, Song Z, Willett MH, et al. Serum amyloid a regulates granulomatous inflammation in sarcoidosis through toll-like receptor-2. Am J Respir Crit Care Med 2010;181(4):360-373. doi:10.1164/rccm.200905-0696OC
49. Sharp M, Donnelly SC, Moller DR. Tocilizumab in sarcoidosis patients failing steroid sparing therapies and anti-TNF agents. Respir Med X 2019;1(February):100004. doi:10.1016/j.yrmex.2019.100004
50. Damsky W, Thakral D, Emeagwali N, Galan A, King B. Tofacitinib Treatment and Molecular Analysis of Cutaneous Sarcoidosis. New England Journal of Medicine 2018;379(26):2540-2546. doi:10.1056/nejmoa1805958
Article Sidebar
Article Details
How to Cite
This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License.
This is an Open Access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by-nc/4.0) which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
Transfer of Copyright and Permission to Reproduce Parts of Published Papers.
Authors retain the copyright for their published work. No formal permission will be required to reproduce parts (tables or illustrations) of published papers, provided the source is quoted appropriately and reproduction has no commercial intent. Reproductions with commercial intent will require written permission and payment of royalties.
This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License.