[en] Regulatory B cells (Bregs) producing IL-10 have negative regulatory function. Several studies have shown the important roles for Toll-like receptor 2 (TLR2), TLR4, and TLR9 ligation in the development of Bregs. We have reported that Schistosome soluble egg antigen (SEA) induced the production of Bregs. However, it remains unclear whether such activation is via the TLR pathway. The present study showed that IL-10 and TLR4 mRNA expression in spleen B cells of significantly increased in C57BL/10 J mice spleen B cells following SEA stimulation. The level of secreted IL-10 and IL-10+ B cell proportion decreased in spleen B cells derived from TLR4-deficient C57BL/10ScNJ (TLR4-/-) mice following SEA or LPS stimulation compared with C57BL/10 J mice. The CD1dhiCD5+ B cells proportion decreased in spleen B cells of TLR4-/- mice following SEA stimulation compared with control mice. NF-κB, ERK, p38MAPK and JNK signal transduction inhibitors significantly suppressed IL-10 secretion in CD1dhiCD5+ B cells induced by SEA or LPS. The phosphorylation levels of IκBα, p65, ERK, JNK and p38 were increased in CD1dhiCD5+ B cell of C57BL/10 J mice treated with LPS or SEA. In conclusion, this study suggests that TLR4 plays a critical role in Bregs activation induced by SEA. And the TLR4-triggered NF-κB and MAPK pathways activation in CD1dhiCD5+ B cells stimulated with SEA. The findings elucidated the mechanism of SEA induction of CD1dhiCD5+ B cells and helped us to understand the immune regulation during Schistosoma japonicum infection.
Disciplines :
Immunology & infectious disease
Author, co-author :
Tian, Fang; Department of Pathogen Biology and Immunology, Institute of Translational Medicine, Medical college, Yangzhou University, Yangzhou 225001, China, Jiangsu Key Laboratory of Experimental & Translational Non-coding RNA Research, Yangzhou 225001, China, Jiangsu Key Laboratory of Zoonosis, Yangzhou 225001, China. Electronic address: ftian@yzu.edu.cn
Xian, Kangwen; Department of Pathogen Biology and Immunology, Institute of Translational Medicine, Medical college, Yangzhou University, Yangzhou 225001, China, Department of Psychiatry, Affiliated Wu Tai Shan Hospital of Medical College of Yangzhou University, Yangzhou 225003, China
Yang, Bin ; Université de Liège - ULiège > Fundamental and Applied Research for Animals and Health (FARAH) ; Department of Pathogen Biology and Immunology, Institute of Translational Medicine, Medical college, Yangzhou University, Yangzhou 225001, China
Duan, Qiufang; Department of Pathogen Biology and Immunology, Institute of Translational Medicine, Medical college, Yangzhou University, Yangzhou 225001, China
Qian, Li; Department of Pathogen Biology and Immunology, Institute of Translational Medicine, Medical college, Yangzhou University, Yangzhou 225001, China, Jiangsu Key Laboratory of Experimental & Translational Non-coding RNA Research, Yangzhou 225001, China, Jiangsu Key Laboratory of Zoonosis, Yangzhou 225001, China
Shi, Chanhong; Department of Neurology, Yiwu Hospital Affiliated to Wenzhou Medical University and Yiwu Central Hospital, YiWu 322000, China. Electronic address: chanhongs@163.com
Language :
English
Title :
Deficiency in TLR4 impairs regulatory B cells production induced by Schistosome soluble egg antigen.
NSCF - National Natural Science Foundation of China
Funding text :
This work was supported by the grant from the National Natural Science Foundation of China (grant number 81101265 , 81373130 ) and Basic Public Welfare Research Project of Zhejiang Province (grant number LBY22H200004 ).
Sanches, R.C.O., Souza, C., Oliveira, S.C., Schistosoma antigens as activators of inflammasome pathway: from an unexpected stimulus to an intriguing role. Microbes Infect. 22:10 (2020), 534–539, 10.1016/j.micinf.2020.08.001 〈https://www.ncbi.nlm.nih.gov/pubmed/32841730〉.
Noh, G., Lee, J.H., Regulatory B cells and allergic diseases. Allergy, Asthma Immunol. Res. 3:3 (2011), 168–177, 10.4168/aair.2011.3.3.168 〈https://www.ncbi.nlm.nih.gov/pubmed/21738882〉.
Candando, K.M., Lykken, J.M., Tedder, T.F., B10 cell regulation of health and disease. Immunol. Rev. 259:1 (2014), 259–272, 10.1111/imr.12176 〈https://www.ncbi.nlm.nih.gov/pubmed/24712471〉.
Catalan, D., Mansilla, M.A., Ferrier, A., Soto, L., Oleinika, K., Aguillon, J.C., et al. Immunosuppressive Mechanisms of Regulatory B Cells. Front Immunol., 12, 2021, 611795, 10.3389/fimmu.2021.611795 〈https://www.ncbi.nlm.nih.gov/pubmed/33995344〉.
Iwata, Y., Matsushita, T., Horikawa, M., Dilillo, D.J., Yanaba, K., Venturi, G.M., et al. Characterization of a rare IL-10-competent B-cell subset in humans that parallels mouse regulatory B10 cells. Blood 117:2 (2011), 530–541, 10.1182/blood-2010-07-294249 〈https://www.ncbi.nlm.nih.gov/pubmed/20962324〉.
Dasgupta, S., Dasgupta, S., Bandyopadhyay, M., Regulatory B cells in infection, inflammation, and autoimmunity. Cell Immunol., 352, 2020, 104076, 10.1016/j.cellimm.2020.104076 〈https://www.ncbi.nlm.nih.gov/pubmed/32143836〉.
Tedder, T.F., B10 cells: a functionally defined regulatory B cell subset. J. Immunol. 194:4 (2015), 1395–1401, 10.4049/jimmunol.1401329 〈https://www.ncbi.nlm.nih.gov/pubmed/25663677〉.
van der Vlugt, L.E., Labuda, L.A., Ozir-Fazalalikhan, A., Lievers, E., Gloudemans, A.K., Liu, K.Y., et al. Schistosomes induce regulatory features in human and mouse CD1d(hi) B cells: inhibition of allergic inflammation by IL-10 and regulatory T cells. PloS One, 7(2), 2012, e30883, 10.1371/journal.pone.0030883 〈https://www.ncbi.nlm.nih.gov/pubmed/22347409〉.
Xiao, J., Guan, F., Sun, L., Zhang, Y., Zhang, X., Lu, S., et al. B cells induced by Schistosoma japonicum infection display diverse regulatory phenotypes and modulate CD4(+) T cell response. Parasit. Vectors, 13(1), 2020, 147, 10.1186/s13071-020-04015-3 〈https://www.ncbi.nlm.nih.gov/pubmed/32197642〉.
Tian, F., Hu, X., Xian, K., Zong, D., Liu, H., Wei, H., et al. B10 cells induced by Schistosoma japonicum soluble egg antigens modulated regulatory T cells and cytokine production of T cells. Parasitol. Res. 114:10 (2015), 3827–3834, 10.1007/s00436-015-4613-x 〈https://www.ncbi.nlm.nih.gov/pubmed/26149531〉.
Haeberlein, S., Obieglo, K., Ozir-Fazalalikhan, A., Chaye, M.A.M., Veninga, H., van der Vlugt, L., et al. Schistosome egg antigens, including the glycoprotein IPSE/alpha-1, trigger the development of regulatory B cells. PLoS Pathog., 13(7), 2017, e1006539, 10.1371/journal.ppat.1006539 〈https://www.ncbi.nlm.nih.gov/pubmed/28753651〉.
Obieglo, K., Costain, A., Webb, L.M., Ozir-Fazalalikhan, A., Brown, S.L., MacDonald, A.S., et al. Type I interferons provide additive signals for murine regulatory B cell induction by Schistosoma mansoni eggs. Eur. J. Immunol. 49:8 (2019), 1226–1234, 10.1002/eji.201847858 〈https://www.ncbi.nlm.nih.gov/pubmed/31099896〉.
Mauri, C., Bosma, A., Immune regulatory function of B cells. Annu. Rev. Immunol. 30 (2012), 221–241, 10.1146/annurev-immunol-020711-074934 〈https://www.ncbi.nlm.nih.gov/pubmed/22224776〉.
Bocian, K., Kiernozek, E., Domagala-Kulawik, J., Korczak-Kowalska, G., Stelmaszczyk-Emmel, A., Drela, N., Expanding Diversity and Common Goal of Regulatory T and B Cells. I: Origin, Phenotype, Mechanisms. Arch. Immunol. Ther. Exp. (Warsz. ) 65:6 (2017), 501–520, 10.1007/s00005-017-0469-3 〈https://www.ncbi.nlm.nih.gov/pubmed/28477096〉.
van der Vlugt, L.E., Haeberlein, S., de Graaf, W., Martha, T.E., Smits, H.H., Toll-like receptor ligation for the induction of regulatory B cells. Methods Mol. Biol. 1190 (2014), 127–141, 10.1007/978-1-4939-1161-5_10 〈https://www.ncbi.nlm.nih.gov/pubmed/25015278〉.
Khan, A.R., Amu, S., Saunders, S.P., Hams, E., Blackshields, G., Leonard, M.O., et al. Ligation of TLR7 on CD19(+) CD1d(hi) B cells suppresses allergic lung inflammation via regulatory T cells. Eur. J. Immunol. 45:6 (2015), 1842–1854, 10.1002/eji.201445211 〈https://www.ncbi.nlm.nih.gov/pubmed/25763771〉.
Lampropoulou, V., Hoehlig, K., Roch, T., Neves, P., Calderon Gomez, E., Sweenie, C.H., et al. TLR-activated B cells suppress T cell-mediated autoimmunity. J. Immunol. 180:7 (2008), 4763–4773, 10.4049/jimmunol.180.7.4763 〈https://www.ncbi.nlm.nih.gov/pubmed/18354200〉.
Zhang, M., Gao, Y., Du, X., Zhang, D., Ji, M., Wu, G., Toll-like receptor (TLR) 2 and TLR4 deficiencies exert differential in vivo effects against Schistosoma japonicum. Parasite Immunol. 33:4 (2011), 199–209, 10.1111/j.1365-3024.2010.01265.x 〈https://www.ncbi.nlm.nih.gov/pubmed/21392041〉.
Boros, D.L., Warren, K.S., Delayed hypersensitivity-type granuloma formation and dermal reaction induced and elicited by a soluble factor isolated from Schistosoma mansoni eggs. J. Exp. Med. 132:3 (1970), 488–507, 10.1084/jem.132.3.488 〈https://www.ncbi.nlm.nih.gov/pubmed/5535626〉.
Livak, K.J., Schmittgen, T.D., Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) Method. Methods 25:4 (2001), 402–408, 10.1006/meth.2001.1262 〈https://www.ncbi.nlm.nih.gov/pubmed/11846609〉.
Rosser, E.C., Blair, P.A., Mauri, C., Cellular targets of regulatory B cell-mediated suppression. Mol. Immunol. 62:2 (2014), 296–304, 10.1016/j.molimm.2014.01.014 〈https://www.ncbi.nlm.nih.gov/pubmed/24556109〉.
Mauri, C., Menon, M., The expanding family of regulatory B cells. Int. Immunol. 27:10 (2015), 479–486, 10.1093/intimm/dxv038 〈https://www.ncbi.nlm.nih.gov/pubmed/26071023〉.
Jansen, K., Cevhertas, L., Ma, S., Satitsuksanoa, P., Akdis, M., van de Veen, W., Regulatory B cells, A to Z. Allergy 76:9 (2021), 2699–2715, 10.1111/all.14763 〈https://www.ncbi.nlm.nih.gov/pubmed/33544905〉.
van der Kleij, D., Latz, E., Brouwers, J.F., Kruize, Y.C., Schmitz, M., Kurt-Jones, E.A., et al. A novel host-parasite lipid cross-talk. Schistosomal lyso-phosphatidylserine activates toll-like receptor 2 and affects immune polarization. J. Biol. Chem. 277:50 (2002), 48122–48129, 10.1074/jbc.M206941200 〈https://www.ncbi.nlm.nih.gov/pubmed/12359728〉.
Thomas, P.G., Carter, M.R., Atochina, O., Da'Dara, A.A., Piskorska, D., McGuire, E., et al. Maturation of dendritic cell 2 phenotype by a helminth glycan uses a Toll-like receptor 4-dependent mechanism. J. Immunol. 171:11 (2003), 5837–5841, 10.4049/jimmunol.171.11.5837 〈https://www.ncbi.nlm.nih.gov/pubmed/14634093〉.
Kane, C.M., Jung, E., Pearce, E.J., Schistosoma mansoni egg antigen-mediated modulation of Toll-like receptor (TLR)-induced activation occurs independently of TLR2, TLR4, and MyD88. Infect. Immun. 76:12 (2008), 5754–5759, 10.1128/IAI.00497-08 〈https://www.ncbi.nlm.nih.gov/pubmed/18824534〉.
Barr, T.A., Brown, S., Ryan, G., Zhao, J., Gray, D., TLR-mediated stimulation of APC: Distinct cytokine responses of B cells and dendritic cells. Eur. J. Immunol. 37:11 (2007), 3040–3053, 10.1002/eji.200636483 〈https://www.ncbi.nlm.nih.gov/pubmed/17918201〉.
Velupillai, P., Harn, D.A., Oligosaccharide-specific induction of interleukin 10 production by B220+ cells from schistosome-infected mice: a mechanism for regulation of CD4+ T-cell subsets. Proc. Natl. Acad. Sci. USA 91:1 (1994), 18–22, 10.1073/pnas.91.1.18 〈https://www.ncbi.nlm.nih.gov/pubmed/7904066〉.
Velupillai, P., Secor, W.E., Horauf, A.M., Harn, D.A., B-1 cell (CD5+B220+) outgrowth in murine schistosomiasis is genetically restricted and is largely due to activation by polylactosamine sugars. J. Immunol. 158:1 (1997), 338–344 〈https://www.ncbi.nlm.nih.gov/pubmed/8977208〉.
Wang, K., Tao, L., Su, J., Zhang, Y., Zou, B., Wang, Y., et al. TLR4 supports the expansion of FasL(+)CD5(+)CD1d(hi) regulatory B cells, which decreases in contact hypersensitivity. Mol. Immunol. 87 (2017), 188–199, 10.1016/j.molimm.2017.04.016 〈https://www.ncbi.nlm.nih.gov/pubmed/28505514〉.
Okada, Y., Ochi, H., Fujii, C., Hashi, Y., Hamatani, M., Ashida, S., et al. Signaling via toll-like receptor 4 and CD40 in B cells plays a regulatory role in the pathogenesis of multiple sclerosis through interleukin-10 production. J. Autoimmun. 88 (2018), 103–113, 10.1016/j.jaut.2017.10.011 〈https://www.ncbi.nlm.nih.gov/pubmed/29146546〉.
Qin, X., Jiang, X., Jiang, X., Wang, Y., Miao, Z., He, W., et al. Micheliolide inhibits LPS-induced inflammatory response and protects mice from LPS challenge. Sci. Rep., 6, 2016, 23240, 10.1038/srep23240 〈https://www.ncbi.nlm.nih.gov/pubmed/26984741〉.
Lai, J.L., Liu, Y.H., Liu, C., Qi, M.P., Liu, R.N., Zhu, X.F., et al. Indirubin Inhibits LPS-Induced Inflammation via TLR4 Abrogation Mediated by the NF-kB and MAPK Signaling Pathways. Inflammation 40:1 (2017), 1–12, 10.1007/s10753-016-0447-7 〈https://www.ncbi.nlm.nih.gov/pubmed/27718095〉.
Gerondakis, S., Strasser, A., The role of Rel/NF-kappaB transcription factors in B lymphocyte survival. Semin. Immunol. 15:3 (2003), 159–166, 10.1016/s1044-5323(03)00036-8 〈https://www.ncbi.nlm.nih.gov/pubmed/14563114〉.