JAK/STAT信号通路在肠黏膜再生及调节辅助性T细胞应答中的研究进展

doi:10.16431/j.cnki.1671-7236.2022.06.008

Abstract

Abstract: As the junction of the internal and external environment in the body, the intestine is susceptible to various toxic and harmful substances from outside, which leads to damage to the epithelial structure, function and microecosystem, and then reduces growth performance of animals and economic benefit.Intestinal stem cell (ISC)-driven intestinal cell renewal at the base of the crypt is the driving force for the epithelial structure and is necessary for the repair after intestinal injury.ISCs activity are synergistically regulated by various molecular signals in the ISCs microenvironment.And the Janu kinase/signal transducer and activator of transcription (JAK/STAT) pathway is a common pathway for multiple cytokine signals, which bind to tyrosine kinase-related receptors to activate JAK, and then phosphorylate STAT and trigger the transcription of target genes such as cycle-related and anti-apoptotic proteins to control ISCs proliferation, apoptosis, and differentiation fate and ultimately maintains the ordered structure of the crypt villi axis.In addition, helper T cells (Th cells) around the ISCs secrete interleukins (ILs) and interferons (IFNs) in crosstalk with the JAK/STAT signaling pathway in ISCs to achieve a rapid response of intestinal cells to injury stimuli, which accelerates ISCs division and promote intestinal epithelial regeneration.This review focused on the mechanisms of JAK/STAT-mediated ISCs in maintaining the structural and functional integrity of the intestinal epithelium and how Th cells regulate the differentiation of ISCs to functional cells.Meanwhile, the authors described abnormal changes in this signaling pathway during the occurrence of certain livestock and poultry diseases, and identify emerging research models such as intestinal organoids into the study and practice of animal intestinal development and disease diagnosis.The accurate control of JAK/STAT is expected to reveal the updating regularity of the crypt-villus axis and provide the theoretical basis for establishing the scientific nutritional technology scheme and improving intestinal health.

Key words: JAK/STAT signal pathway; intestinal stem cell; helper T cell; intestinal epithelial regeneration

CLC Number:

Q593

ZAN Gengxiu, QIN Yingchao, ZHU Chao, WANG Xiuqi. Research Progress of JAK/STAT Signal Pathway Regulating Intestinal Mucosal Regeneration and Helper T Cell Response[J]. China Animal Husbandry and Veterinary Medicine, 2022, 49(6): 2079-2087.

References

[1] ZHOU J Y, LIN H L, WANG Z, et al.Zinc L-aspartate enhances intestinal stem cell activity to protect the integrity of the intestinal mucosa against deoxynivalenol through activation of the Wnt/β-catenin signaling pathway[J].Environmental Pollution, 2020, 262:114290.
[2] ZHOU J Y, HUANG D G, ZHU M, et al.Wnt/β-catenin-mediated heat exposure inhibits intestinal epithelial cell proliferation and stem cell expansion through endoplasmic reticulum stress[J].Journal of Cellular Physiology, 2020, 235(7-8):5613-5627.
[3] HERRERA S C, BACH E A.JAK/STAT signaling in stem cells and regeneration:From Drosophila to vertebrates[J].Development, 2019, 146(2):dev167643.
[4] ZHOU F, RASMUSSEN A, LEE S, et al.The UPD3 cytokine couples environmental challenge and intestinal stem cell division through modulation of JAK/STAT signaling in the stem cell microenvironment[J].Developmental Biology, 2013, 373(2):383-93.
[5] RAJENDRAN P, LI F, SHANMUGAM M K, et al.Celastrol suppresses growth and induces apoptosis of human hepatocellular carcinoma through the modulation of STAT3/JAK2 signaling cascade in vitro and in vivo[J].Cancer Prevention Research, 2012, 5(4):631-643.
[6] SONG Z W, JIN C L, YE M, et al.Lysine inhibits apoptosis in satellite cells to govern skeletal muscle growth via the JAK2-STAT3 pathway[J].Food & Function, 2020, 11(5):3941-3951.
[7] 陈俊杰, 安云飞, 赵晓东.JAK-STAT信号通路与单基因遗传病[J].中国实用儿科杂志, 2021, 36(4):308-314. CHEN J J, AN Y F, ZHAO X D.JAK-STAT signaling pathway and monogenic disease[J].Chinese Journal of Practical Pediatrics, 2021, 36(4):308-314.(in Chinese)
[8] KISSELEVA T, BHATTACHARYA S, BRAUNSTEIN J, et al.Signaling through the JAK/STAT pathway, recent advances and future challenges[J].Gene, 2002, 285(1-2):1-24.
[9] MD G, CARNEROS D, GARBERS C, et al.New insights into IL-6 family cytokines in metabolism, hepatology and gastroenterology[J].Nature Reviews Gastroenterology & Hepatology, 2021, 18(11):787-803.
[10] FAN L, ZHOU L.Anti-IL-23 exerted protective effects on cerebral ischemia-reperfusion injury through JAK2/STAT3 signaling pathway[J].Molecular Biology Reports, 2021, 48(4):3475-3484.
[11] SINGH K, PIPRODE V, MHASKE S T, et al.IL-3 differentially regulates membrane and soluble RANKL in osteoblasts through metalloproteases and the JAK2/STAT5 pathway and improves the RANKL/OPG ratio in adult mice[J].Journal of Immunology, 2018, 200(2):595-606.
[12] ZHOU Y, LI C, LI D, et al.IL-5 blocks apoptosis and tau hyperphosphorylation induced by a β peptide in PC12 cells[J].Journal of Physiology and Biochemistry, 2017, 73(2):259-266.
[13] PATEL A B, FRANZINI A, LEROY E, et al.JAK2 ex13InDel drives oncogenic transformation and is associated with chronic eosinophilic leukemia and polycythemia vera[J].Blood, 2019, 134(26):2388-2398.
[14] SPRINGUEL L, RENAULD J C, KNOOPS L.JAK kinase targeting in hematologic malignancies:A sinuous pathway from identification of genetic alterations towards clinical indications[J].Haematologica, 2015, 100(10):1240-1253.
[15] DENGLER H S, WU X, PENG I, et al.Lung-restricted inhibition of Janus kinase 1 is effective in rodent models of asthma[J].Science Translational Medicine, 2018, 10(468):eaao2151.
[16] PIETSCHKE K, HOLSTEIN J, MEIER K, et al.The inflammation in cutaneous lichen planus is dominated by IFN-γ and IL-21-A basis for therapeutic JAK1 inhibition[J].Experimental Dermatology, 2021, 30(2):262-270.
[17] TRIVELLA D B, FERREIRA-JÚNIOR J R, DUMOUTIER L, et al.Structure and function of interleukin-22 and other members of the interleukin-10 family[J].Cellular and Molecular Life Sciences, 2010, 67(17):2909-2935.
[18] TRUONG A D, HONG Y, HOANG C T, et al.Chicken IL-26 regulates immune responses through the JAK/STAT and NF-κB signaling pathways[J].Developmental and Comparative Immunology, 2017, 73:10-20.
[19] DE JONGE W J, VAN DER ZANDEN E P, THE F O, et al.Stimulation of the vagus nerve attenuates macrophage activation by activating the JAK2-STAT3 signaling pathway[J].Nature Immunology, 2005, 6(8):844-851.
[20] SEIF F, KHOSHMIRSAFA M, AAZAMI H, et al.The role of JAK-STAT signaling pathway and its regulators in the fate of T helper cells[J].Cell Communication & Signaling, 2017, 15(1):23.
[21] HUANG J, MA G, ZHU M, et al.Molecular characterization of the porcine STAT4 and STAT6 genes[J].Molecular Biology Reports, 2012, 39(6):6959-6965.
[22] HVNTELMANN B, STAAB J, HERRMANN-LINGEN C, et al.A conserved motif in the linker domain of STAT1 transcription factor is required for both recognition and release from high-affinity DNA-binding sites[J].PLoS One, 2014, 9(5):e97633.
[23] VALENTINO L, PIERRE J.JAK/STAT signal transduction:Regulators and implication in hematological malignancies[J].Biochemical Pharmacology, 2006, 71(6):713-721.
[24] YOSHIMURA A, ITO M, MISE-OMATA S, et al.SOCS:Negative regulators of cytokine signaling for immune tolerance[J].International Immunology, 2021, 33(12):711-716.
[25] MATSUMOTO A, SEKI Y, KUBO M, et al.Suppression of STAT5 functions in liver, mammary glands, and T cells in cytokine-inducible SH2-containing protein 1 transgenic mice[J].Cellular and Molecular Biology, 1999, 19(9):6396-6407.
[26] YASUKAWA H, SASAKI A, YOSHIMURA A.Negative regulation of cytokine signaling pathways[J].Annual Review of Immunology, 2000, 18:143-164.
[27] MIURA K, WAKAYAMA Y, TANINO M, et al.Involvement of EphA2-mediated tyrosine phosphorylation of Shp2 in Shp2-regulated activation of extracellular signal-regulated kinase[J].Oncogene, 2013, 32:5292-5301.
[28] CONCHA-BENAVENTE F, SRIVASTAVA R M, FERRONE S, et al.EGFR-mediated tumor immunoescape:The imbalance between phosphorylated STAT1 and phosphorylated STAT3[J].Oncoimmu-nology, 2013, 2(12):e27215.
[29] LI L, MODI H, MCDONALD T, et al.A critical role for SHP2 in STAT5 activation and growth factor-mediated proliferation, survival, and differentiation of human CD34⁺ cells[J].Blood, 2011, 118:1504-1515.
[30] NIU G J, XU J D, YUAN W J, et al.Protein inhibitor of activated STAT (PIAS) negatively regulates the JAK/STAT pathway by inhibiting STAT phosphorylation and translocation[J].Frontiers in Immunology, 2018, 9:2392.
[31] LU S N, PENG X, ZENG S, et al.Grass carp (Ctenopharyngodon idellus) PIAS1 inhibits innate immune response via interacting with STAT1[J].Developmental and Comparative Immunology, 2021, 125:104216.
[32] POLIMENO L, FRANCAVILLA A, PISCITELLI D, et al.The role of PIAS3, p-STAT3 and ALR in colorectal cancer:New translational molecular features for an old disease[J].European Review for Medical and Pharmacological Sciences, 2020, 24(20):10496-10511.
[33] LEEDHAM S J, BRITTAN M, MCDONALD S A C, et al.Intestinal stem cells[J].Journal of Cellular & Molecular Medicine, 2010, 9(1):11-24.
[34] DU G, XIONG L, LI X.et al.Peroxisome elevation induces stem cell differentiation and intestinal epithelial repair[J].Developmental Cell, 2020, 53:169-184.
[35] BOWMAN T, GARCIA R, TURKSON J, et al.STATs in oncogenesis[J].Oncogene, 2000, 19(21):2474-2488.
[36] GUO X, HUANG H, YANG Z, et al.Division of labor:Roles of groucho and CtBP in Notch-mediated lateral inhibition that controls intestinal stem cell differentiation in Drosophila[J].Stem Cell Reports, 2019, 12(5):1007-1023.
[37] BEEBE K, LEE W C, MICCHELLI C A.JAK/STAT signaling coordinates stem cell proliferation and multilineage differentiation in the Drosophila intestinal stem cell lineage[J].Developmental Biology, 2010, 338(1):28-37.
[38] LIU W, SINGH S R, HOU S X.JAK-STAT is restrained by Notch to control cell proliferation of the Drosophila intestinal stem cells[J].Journal of Cellular Biochemistry, 2010, 109(5):992-999.
[39] JIANG H, PATEL P H, KOHLMAIER A, et al.Cytokine/Jak/STAT signaling mediates regeneration and homeostasis in the Drosophila midgut[J].Cell, 2009, 137(7):1343-1355.
[40] GILBERT S, NIVARTHI H, MAYHEW C N, et al.Activated STAT5 confers resistance to intestinal injury by increasing intestinal stem cell proliferation and regeneration[J].Stem Cell Reports, 2015, 4(2):209-225.
[41] GILBERT S, ZHANG R, DENSON L, et al.Enterocyte STAT5 promotes mucosal wound healing via suppression of myosin light chain kinase-mediated loss of barrier function and inflammation[J].EMBO Molecular Medicine, 2012, 4(2):109-124.
[42] RICHMOND C A, RICKNER H, SHAH M S, et al.JAK/STAT-1 signaling is required for reserve intestinal stem cell activation during intestinal regeneration following acute inflammation[J].Stem Cell Reports, 2018, 10(1):17-26.
[43] LINDEMANS C A, CALAFIORE M, MERTEL-SMANN A M, et al.Interleukin-22 promotes intestinal-stem-cell-mediated epithelial regeneration[J].Nature, 2015, 528(7853):560-564.
[44] GUHA P, GARDELL J, DARPOLOR J, et al.STAT3 inhibition induces Bax-dependent apoptosis in liver tumor myeloid-derived suppressor cells[J].Oncogene, 2019, 38(4):533-548.
[45] HAN X, BENIGHT N, OSUNTOKUN B, et al.Tumour necrosis factor alpha blockade induces an anti-inflammatory growth hormone signalling pathway in experimental colitis[J].Gut, 2007, 56(1):73-81.
[46] HAN X, GILBERT S, GROSCHWITZ K, et al.Loss of GM-CSF signalling in non-haematopoietic cells increases NSAID ileal injury[J].Gut, 2010, 59(8):1066-1078.
[47] LIANG L, XIONG Q, KONG J, et al.Intraperitoneal supplementation of iron alleviates dextran sodium sulfate-induced colitis by enhancing intestinal barrier function[J].Biomedicine & Pharmacotherapy, 2021, 144:112253.
[48] 王瑞娟, 彭瑞云, 高亚兵, 等.IL-11保护中子照射后肠上皮损伤的JAK/STAT信号转导机制研究[J].细胞与分子免疫学杂志, 2009, 25(1):27-30. WANG R J, PENG R Y, GAO Y B, et al.Jak/STAT signaling pathway of IL-11 in the protection of intestinal epithelial cells from neutron radiation[J].Chinese Journal of Cellular and Molecular Immunology, 2009, 25(1):27-30.(in Chinese)
[49] BAI J, BAI J, YANG M.Interleukin-22 attenuates acute pancreatitis-associated intestinal mucosa injury in mice via STAT3 activation[J].Gut and Liver, 2021, 15(5):771-781.
[50] WANG Y, MUMM J B, HERBST R, et al.IL-22 increases permeability of intestinal epithelial tight junctions by enhancing Claudin-2 expression[J].Journal of Immunology, 2017, 199(9):3316-3325.
[51] 秦颖超, 宋志文, 朱敏, 等.谷氨酸通过保护回肠结构完整性增强猪回肠屏障功能[J].动物营养学报, 2020, 32(5):2101-2107. QIN Y C, SONG Z W, ZHU M, et al.Glutamate enhances porcine heal barrier function via protecting heal structural integrality[J].Chinese Journal of Animal Nutrition, 2020, 32(5):2101-2107.(in Chinese)
[52] HARA S, TSUJIKAWA M, MARUYAMA K, et al.STAT3 signaling maintains homeostasis through a barrier function and cell survival in corneal endothelial cells[J].Experimental Eye Research, 2019, 179:132-141.
[53] WANG Z, LI R, TAN J, et al.Syndecan-1 acts in synergy with tight junction through STAT3 signaling to maintain intestinal mucosal barrier and prevent bacterial translocation[J].Inflammatory Bowel Diseases, 2015, 21(8):1894-1907.
[54] YANG F L, WANG D N, LI Y, et al.Th1/Th2 balance and Th17/Treg-mediated immunity in relation to murine resistance to dextran sulfate-induced colitis[J].Journal of Immunology Research, 2017, 2017:7047201.
[55] CHEN Y F, ZHENG J J, QU C, et al.Inonotus obliquus polysaccharide ameliorates dextran sulphate sodium induced colitis involving modulation of Th1/Th2 and Th17/Treg balance[J].Artificial Cells Nanomedicine and Biotechnology, 2019, 47(1):757-766.
[56] BANIK S, RAKSHIT S, SARKAR K.The role of STAT1 in T helper cell differentiation during breast cancer progression[J].Journal of Breast Cancer, 2021, 24(3):253-265.
[57] KARPATHIOU G, PAPOUDOU-BAI A, FERRAND E, et al.STAT6:A review of a signaling pathway implicated in various diseases with a special emphasis in its usefulness in pathology[J].Pathology Research and Practice, 2021, 223:153477.
[58] AYELIGN B, AKALU Y, TEFERI B, et al.Helminth induced immunoregulation and novel therapeutic avenue of allergy[J].Journal of Asthma and Allergy, 2020, 13:439-451.
[59] BYSTROM J, TAHER T E, MUHYADDIN M S, et al.Harnessing the therapeutic potential of Th17 cells[J].Mediators of Inflammation, 2015, 2015:205156.
[60] ZHAO Y, LUAN H, JIANG H, et al.Gegen Qinlian decoction relieved DSS-induced ulcerative colitis in mice by modulating Th17/Treg cell homeostasis via suppressing IL-6/JAK2/STAT3 signaling[J].Phytomedicine, 2021, 84:153519.
[61] SI J, COLLINS S J.IL-3-induced enhancement of retinoic acid receptor activity is mediated through STAT5, which physically associates with retinoic acid receptors in an IL-3-dependent manner[J].Blood, 2002, 100(13):4401-4409.
[62] DIKIY S, LI J, BAI L, et al.A distal FoxP3 enhancer enables interleukin-2 dependent thymic Treg cell lineage commitment for robust immune tolerance[J].Immunity, 2021, 54(5):931-946.
[63] BITON M, HABER A L, ROGEL N, et al.T Helper cell cytokines modulate intestinal stem cell renewal and differentiation[J].Cell, 2018, 175(5):1307-1320.
[64] HABERMAN Y, SCHIRMER M, DEXHEIMER P J, et al.Age-of-diagnosis dependent ileal immune intensification and reduced alpha-defensin in older versus younger pediatric Crohn disease patients despite already established dysbiosis[J].Mucosal Immunology, 2019, 12(2):491-502.
[65] MA J, CHEN T, MANDELIN J, et al.Regulation of macrophage activation[J].Cellular and Molecular Life Sciences, 2003, 60(11):2334-2346.
[66] CHEN Q Q, YAN L, WANG C Z, et al.Mesenchymal stem cells alleviate TNBS-induced colitis by modulating inflammatory and autoimmune responses[J].World Journal of Gastroenterology, 2013, 19(29):4702-4717.
[67] NIO D F, SODHI C P, EGAN C E, et al.Retinoic acid improves incidence and severity of necrotizing enterocolitis by lymphocyte balance restitution and repopulation of Lgr5⁺ intestinal stem cells[J].Shock, 2017, 47(1):22-32.
[68] SAXENA M, SHIVDASANI R A.Epigenetic signatures and plasticity of intestinal and other stem cells[J].Annual Review of Physiology, 2021, 83:405-427.
[69] YANG L, HE J, WANG R, et al.Nonstructural protein 11 of Porcine reproductive and respiratory syndrome virus induces STAT2 degradation to inhibit interferon signaling[J].Journal of Virology, 2019, 93(22):e01352-19.
[70] RIERA E, PÉREZ-NČU'EZ D, GARCÍA-BELMONTE R, et al.African swine fever virus induces STAT1 and STAT2 degradation to counteract IFN-Ⅰ signaling[J].Frontiers in Microbiology, 2021, 12:722952.
[71] ZHU X, WANG D, ZHOU J, et al.Porcine delta corona virus NSP5 antagonizes type Ⅰ interferon signaling by cleaving STAT2[J].Journal of Virology, 2017, 91(10):e00003-17.
[72] LI L, XUE M, FU F, et al.IFN-lambda 3 mediates antiviral protection against Porcine epidemic diarrhea virus by inducing a distinct antiviral transcript profile in porcine intestinal epithelia[J] .Frontiers in Immunology, 2019, 10:2394.
[73] ZHAO M Z, LI L, ZHAI L H, et al.Comparative transcriptomic and proteomic analyses prove that IFN-λ1 is a more potent inducer of ISGs than IFN-α against Porcine epidemic diarrhea virus in porcine intestinal epithelial cells[J].Journal of Proteome Research, 2020, 19:3697-3707.
[74] LIN H X, LI B, CHEN L, et al.Differential protein analysis of IPEC-J2 cells infected with Porcine epidemic diarrhea virus pandemic and classical strains elucidates the pathogenesis of infection[J].Journal of Proteome Research, 2017, 16:2113-2120.
[75] AN K, FANG L, LUO R, et al.Quantitative proteomic analysis reveals that Transmissible gastroenteritis virus activates the JAK-STAT1 signaling pathway[J].Journal of Proteome Research.2014;13(12):5376-5390.
[76] ZHANG B B, GAN L P, SHAHID M S, et al.In vivo and protective effect of arginine against intestinal inflammatory response induced by in broiler chickens[J].Journal of Animal Science and Biotechnology, 2019, 10:73.
[77] TRUONG A D, RENGARAJ D, HONG Y, et al.Differentially expressed JAK-STAT signaling pathway genes and target microRNAs in the spleen of necrotic enteritis-afflicted chicken lines[J].Research in Veterinary Science, 2017, 115:235-243.

Research Progress of JAK/STAT Signal Pathway Regulating Intestinal Mucosal Regeneration and Helper T Cell Response

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