ER stress activation in the intestinal mucosa but not in mesenteric adipose tissue is associated with inflammation in Crohn’s disease patients
Autoři:
Andressa Coope aff001; Lívia Bitencourt Pascoal aff001; José Diego Botezelli aff001; Francesca Aparecida Ramos da Silva aff001; Maria de Lourdes Setsuko Ayrizono aff001; Bruno Lima Rodrigues aff001; Marciane Milanski aff002; Rita Barbosa Carvalho aff003; João José Fagundes aff001; Lício Augusto Velloso aff004; Raquel Franco Leal aff001
Působiště autorů:
IBD Research Laboratory, Colorectal Surgery Unit, School of Medical Sciences, University of Campinas (UNICAMP), Campinas, São Paulo, Brazil
aff001; Laboratory of Metabolic Disorders, School of Applied Sciences, University of Campinas (UNICAMP), Limeira, São Paulo, Brazil
aff002; Department of Pathology, Gastrocenter, School of Medical Sciences, University of Campinas (UNICAMP), Campinas, São Paulo, Brazil
aff003; Laboratory of Cell Signaling, School of Medical Sciences, University of Campinas (UNICAMP), Campinas, São Paulo, Brazil
aff004
Vyšlo v časopise:
PLoS ONE 14(9)
Kategorie:
Research Article
doi:
https://doi.org/10.1371/journal.pone.0223105
Souhrn
Chronic/abnormal activation of endoplasmic reticulum (ER) stress is linked to the exacerbation of the inflammatory process and has been recently linked to Crohn’s disease (CD) pathophysiology. We investigated the intestinal mucosa and the mesenteric adipose tissue (MAT) collected from CD patients with active disease (CD group) and from non-IBD patients (CTR group) to study ER stress activation and to address tissue-specific modulation in CD. The intestinal mucosa of CD patients showed an upregulation in the expression of ER stress related genes, including ATF3, DNAJC3, STC2, DDIT3, CALR, HSPA5 and HSP90B1. Results showed that EIF2AK3 gene was upregulated, along with increased protein expression of p-eIF2α and p-eIF2α/eIF2α ratio. Additionally, ERN1 gene expression was upregulated, along with an increased spliced/activated form sXBP1 protein. Despite the upregulation of ATF6 gene expression in the intestinal mucosa of CD patients, no differences were found in ATF6 protein expression. Lastly, the analysis of MAT revealed unchanged levels of ER stress markers along with no differences in the activation of UPR. However, chaperone gene expression was modulated in the MAT of CD patients. To conclude, our results address tissue-specific differences in UPR activation in CD and point the ER stress as an important pro-inflammatory mechanism in CD, specifically in the intestinal mucosa.
Klíčová slova:
Adipose tissue – Crohn's disease – DNA transcription – Gastrointestinal tract – Gene expression – Inflammation – Inflammatory bowel disease – Surgical and invasive medical procedures
Zdroje
1. Loddo I, Romano C. Inflammatory bowel disease: Genetics, epigenetics, and pathogenesis. Front Immunol. 2015; 6:6–11. doi: 10.3389/fimmu.2015.00006
2. Walter P, Ron D. The Unfolded Protein Response: From Stress Pathway to Homeostatic Regulation. Science. 2011; 334:1081–1086. doi: 10.1126/science.1209038 22116877
3. Coope A, Pascoal LB, da Silva FAR, Botezelli JD, Ayrizono MLS, Milanski M, et al. Transcriptional and molecular pathways activated in mesenteric adipose tissue and intestinal mucosa of Crohn’s disease patients. Int J Inflam. 2017; 2017:7646859. doi: 10.1155/2017/7646859 28487813
4. Dias CB, Milanski M, Portovedo M, Horita V, Ayrizono Mde L, Planell N, et al. Defective Apoptosis in Intestinal and Mesenteric Adipose Tissue of Crohn’s Disease Patients. PLoS One. 2014; 9:e98547. doi: 10.1371/journal.pone.0098547 24887376
5. Leal RF, Coy CS, Velloso LA, Dalal S, Portovedo M, Rodrigues VS, et al. Autophagy is decreased in mesenteric fat tissue but not in intestinal mucosae of patients with Crohn’s disease. Cell Tissue Res. 2012; 350:549–552. doi: 10.1007/s00441-012-1491-8 22948252
6. Kaser A, Martínez-Naves E, Blumberg RS. Endoplasmic reticulum stress: Implications for inflammatory bowel disease pathogenesis. Curr Opin Gastroenterol. 2010; 26:318–326. doi: 10.1097/MOG.0b013e32833a9ff1 20495455
7. Todd DJ, Lee AH, Glimcher LH. The endoplasmic reticulum stress response in immunity and autoimmunity. Nat Rev Immunol. 2008; 8:663–674. doi: 10.1038/nri2359 18670423
8. Hotamisligil GS. Endoplasmic Reticulum Stress and the Inflammatory Basis of Metabolic Disease. Cell. 2010; 140:900–917. doi: 10.1016/j.cell.2010.02.034 20303879
9. Zhou H, Zhang Y, Fu Y, Chan L, Lee AS. Novel mechanism of anti-apoptotic function of 78-kDa glucose-regulated protein (GRP78). J Biol Chem. 2011; 286:25687–25696. doi: 10.1074/jbc.M110.212944 21622563
10. Zhu G, Lee AS. Role of the unfolded protein response, GRP78 and GRP94 in organ homeostasis. J Cell Physiol. 2015; 230:1413–1420. doi: 10.1002/jcp.24923 25546813
11. Eletto D, Dersh D, Argon Y. GRP94 in ER quality control and stress responses. Semin Cell Dev Biol. 2010; 21:479–485. doi: 10.1016/j.semcdb.2010.03.004 20223290
12. Kaser A, Lee AH, Franke A, Glickman JN, Zeissig S, Tilg H, et al. XBP1 Links ER Stress to Intestinal Inflammation and Confers Genetic Risk for Human Inflammatory Bowel Disease. Cell. 2008; 134:743–756. doi: 10.1016/j.cell.2008.07.021 18775308
13. Shkoda A, Ruiz PA, Daniel H, Kim SC, Rogler G, Sartor RB, et al. Interleukin-10 Blocked Endoplasmic Reticulum Stress in Intestinal Epithelial Cells: Impact on Chronic Inflammation. Gastroenterology. 2007; 132:190–207. doi: 10.1053/j.gastro.2006.10.030 17241871
14. Urano F, Wang X, Bertolotti A, Zhang Y, Chung P, Harding HP, et al. Coupling of Stress in the Endoplasmic Reticulum to Activation of JNK Protein Kinases by Transmembrane Protein Kinase IRE1. Science. 2000; 287:664–666. doi: 10.1126/science.287.5453.664 10650002
15. Yamazaki H, Hiramatsu N, Hayakawa K, Tagawa Y, Okamura M, Ogata R, et al. Activation of the Akt-NF- KB Pathway by Subtilase Cytotoxin through the ATF6 Branch of the Unfolded Protein Response. J Immunol. 2009; 183:1480–1487. doi: 10.4049/jimmunol.0900017 19561103
16. Deng J, Lu PD, Zhang Y, Scheuner D, Kaufman RJ, Sonenberg N, Harding HP, Ron D. Translational repression mediates activation of nuclear factor kappa B by phosphorylated translation initiation factor 2. Cell Biol. 2004; 24:10161–10168. doi: 10.1128/MCB.24.23.10161–10168.2004
17. Hu P, Han Z, Couvillon AD, Kaufman RJ, Exton JH. Autocrine Tumor Necrosis Factor Alpha Links Endoplasmic Reticulum Stress to the Membrane Death Receptor Pathway through IRE1α-Mediated NF-κB Activation and Down-Regulation of TRAF2 Expression. Mol Cell Biol. 2006; 26:3071–3084. doi: 10.1128/MCB.26.8.3071-3084.2006 16581782
18. Li Y, Schwabe RF, DeVries-Seimon T, Yao PM, Gerbod-Giannone MC, Tall AR, et al. Free cholesterol-loaded macrophages are an abundant source of tumor necrosis factor-α and interleukin-6: Model of NF-κB- and map kinase-dependent inflammation in advanced atherosclerosis. J Biol Chem. 2005; 280:21763–21772. doi: 10.1074/jbc.M501759200 15826936
19. Gregor MF, Hotamisligil GS. Inflammatory mechanisms in obesity. Annu Rev Immunol. 2011; 29:415–45. doi: 10.1146/annurev-immunol-031210-101322 21219177
20. Wang S, Kaufman RJ. The impact of the unfolded protein response on human disease. J Cell Biol 2012; 197:857–867. doi: 10.1083/jcb.201110131 22733998
21. Fortes MA, Marzuca-Nassr GN, Vitzel KF, da Justa Pinheiro CH, Newsholme P, Curi R. Housekeeping proteins: How useful are they in skeletal muscle diabetes studies and muscle hypertrophy models? Anal Biochem. 2016; 1;504:38–40. doi: 10.1016/j.ab.2016.03.023 27060530
22. Romero-Calvo I, Ocón B, Martínez-Moya P, Suárez MD, Zarzuelo A, Martínez-Augustin O, et al. Reversible Ponceau staining as a loading control alternative to actin in Western blots. Anal Biochem. 2010; 401(2):318–20. doi: 10.1016/j.ab.2010.02.036 20206115
23. Wehkamp J, Harder J, Weichenthal M, Schwab M, Schäffeler E, Schlee M, et al. NOD2 (CARD15) mutations in Crohn’s disease are associated with diminished mucosal α-defensin expression. Gut. 2004; 53:1658–1664. doi: 10.1136/gut.2003.032805 15479689
24. Hoefkens E, Nys K, John JM, Van Steen K, Arijs I, Van der Goten J, et al. Genetic association and functional role of Crohn disease risk alleles involved in microbial sensing, autophagy, and endoplasmic reticulum (ER) stress. Autophagy. 2013; 9:2046–2055. doi: 10.4161/auto.26337 24247223
25. Adolph TE, Tomczak MF, Niederreiter L, Ko HJ, Böck J, Martinez-Naves E, et al. Paneth cells as a site of origin for intestinal inflammation. Nature. 2013; 14:503(7475):272–6. doi: 10.1038/nature12599 24089213
26. Van Der Sloot KWJ, Joshi AD, Bellavance DR, Gilpin KK, Stewart KO, Lochhead P, et al. Visceral adiposity, genetic susceptibility, and risk of complications among individuals with Crohn’s disease. Inflamm Bowel Dis. 2017; 23:82–88. doi: 10.1097/MIB.0000000000000978 27893544
27. Bettigole SE, Glimcher LH. Endoplasmic Reticulum Stress in Immunity. Annu Rev Immunol. 2015; 33:107–138. doi: 10.1146/annurev-immunol-032414-112116 25493331
28. Pott J, Maloy KJ. Epithelial autophagy controls chronic colitis by reducing TNF-induced apoptosis. Autophagy. 2018; 8627:1–2. doi: 10.1080/15548627.2018.1450021
29. Jiang H, Wek SA, McGrath BC, Scheuner D, Kaufman RJ, Cavener DR, et al. Phosphorylation of the alpha subunit of eukaryotic initiation factor 2 is required for activation of NF-kappaB in response to diverse cellular stresses. Mol Cell Biol. 2003; 23:5651–63. doi: 10.1128/MCB.23.16.5651-5663.2003 12897138
30. Zeiger W, Ito D, Swetlik C, Oh-hora M, Villereal ML, Thinakaran G. Stanniocalcin 2 Is a Negative Modulator of Store-Operated Calcium Entry. Mol Cell Biol. 2011; 31:3710–3722. doi: 10.1128/MCB.05140-11 21746875
31. Fazio EN, DiMattia GE, Chadi SA, Kernohan KD, Pin CL. Stanniocalcin 2 alters PERK signalling and reduces cellular injury during cerulein induced pancreatitis in mice. BMC Cell Biol. 2011; 5(12):17. doi: 10.1186/1471-2121-12-17
32. Ito D, Walker JR, Thompson CS, Moroz I, Lin W, Veselits ML, et al. Characterization of stanniocalcin 2, a novel target of the mammalian unfolded protein response with cytoprotective properties. Mol Cell Biol. 2004; 24:9456–9469. doi: 10.1128/MCB.24.21.9456-9469.2004 15485913
33. Roobol A, Roobol J, Bastide A, Knight JR, Willis AE, Smales CM. p58 IPK is an inhibitor of the eIF2α kinase GCN2 and its localization and expression underpin protein synthesis and ER processing capacity. Biochem J. 2015; 465:213–225. doi: 10.1042/BJ20140852 25329545
34. Petrova K, Oyadomari S, Hendershot LM, Ron D. Regulated association of misfolded endoplasmic reticulum lumenal proteins with P58/DNAJc3. EMBO J. 2008; 27:2862–2872. doi: 10.1038/emboj.2008.199 18923430
35. Ni M, Zhang Y, Lee AS. Beyond the endoplasmic reticulum: atypical GRP78 in cell viability, signalling and therapeutic targeting. Biochem J. 2011; 434:181–188. doi: 10.1042/BJ20101569 21309747
36. Lee AS. Glucose-regulated proteins in cancer: Molecular mechanisms and therapeutic potential. Nat Rev Cancer. 2014; 14:263–276. doi: 10.1038/nrc3701 24658275
37. Lewy TG, Grabowski JM, Bloom ME. BiP: Master regulator of the unfolded protein response and crucial factor in flavivirus biology. Yale J Biol Med. 2017; 90:291–300. 28656015
38. Maruri-Avidal L, Lopez S, Arias CF. Endoplasmic Reticulum Chaperones Are Involved in the Morphogenesis of Rotavirus Infectious Particles J Virol. 2008; 82:5368–5380. doi: 10.1128/JVI.02751-07 18385250
39. Mimura N, Hamada H, Kashio M, Jin H, Toyama Y, Kimura K, et al. Aberrant quality control in the endoplasmic reticulum impairs the biosynthesis of pulmonary surfactant in mice expressing mutant BiP. Cell Death Differ. 2007; 14:1475–1485. doi: 10.1038/sj.cdd.4402151 17464327
40. Bogaert S, De Vos M, Olievier K, Peeters H, Elewaut D, Lambrecht B, et al. Involvement of endoplasmic reticulum stress in inflammatory bowel disease: A different implication for colonic and ileal disease? PLoS One. 6 2011; 6(10):e25589. doi: 10.1371/journal.pone.0025589 22028783
41. Coffey JC, O’Leary DP. The mesentery: structure, function, and role in disease. Lancet Gastroenterol Hepatol. 2016; 1:238–247. doi: 10.1016/S2468-1253(16)30026-7 28404096
42. Mao R, Kurada S, Gordon IO, Baker ME, Gandhi N, McDonald C, et al. The Mesenteric Fat and Intestinal Muscle Interface: Creeping Fat Influencing Stricture Formation in Crohn's Disease. Inflamm Bowel Dis. 2019; 21:25(3):421–426. doi: 10.1093/ibd/izy331 30346528
Článek vyšel v časopise
PLOS One
2019 Číslo 9
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