LILRA3 is related to monocyte-derived dendritic cell maturation and activation

Document Type : Original Article

Authors

1 Department of Rheumatology, The Second Affiliated Hospital, Zhejiang University School of Medicine, 88 Jiefang Road, Hangzhou, 310009, China

2 Department of Hematology (Cancer Institute, Key Laboratory of Cancer Prevention and Intervention, China National Ministry of Education, Key Laboratory of Molecular Biology in Medical Sciences, Zhejiang Province, China), The Second Affiliated Hospital, Zhejiang University School of Medicine, 88 Jiefang Road, Hangzhou, 310009, China

Abstract

Objective(s): Previously we reported functional leukocyte immunoglobulin-like receptor A3 (LILRA3) leads to susceptibility and sub-phenotypes of several autoimmune diseases. LILRA3 levels in blood serum and CD14+ monocytes enhanced in systemic lupus erythematosus and resulted in disease severity. However, the mechanism of LILRA3 in the pathogenesis of autoimmunity remains elusive. This study aims to explore the potential impact of LILRA3 on the differentiation, maturation, and function of monocyte-derived DCs (MoDCs).
Materials and Methods: The human monocytic cell line (THP-1) was cultured to derive MoDCs in vitro. We performed plasmid transfection to examine the impact of LILRA3 on monocyte differentiation. Surface markers on MoDCs were measured using FACS. To assess the function of mature MoDCs, IL-12p70, IFN-γ and IL-4 levels were detected after the mixed leucocyte response by enzyme-linked immunosorbent assay. Western blot assay was employed in this study to determine the signaling pathways in MoDCs activation.
Results: LILRA3 promotes MoDCs maturation, our results showed significant up-regulation of CD40, CD80, CD86, CD209, and HLA-DR and increased production of pro-inflammatory cytokine IL-12. LILRA3-treated MoDCs exhibited a robust proliferation of allogeneic CD4+ T cells and induced naïve CD4+ T cell polarization into the Th1 phenotype. Furthermore, the preceding activation of MoDCs maturation and LILRA3 function might be attributed to p38 MAPK and STAT1 signaling pathway’s aberrant activation.
Conclusion: This is the first study to report that LILRA3 played a critical role in promoting MoDCs maturation and directing MoDCs to modulate Th1 cell differentiation, which may have a role in the pathogenesis of autoimmune diseases.

Keywords

References

1. Palucka AK, Laupeze B, Aspord C, Saito H, Jego G, Fay J, et al. Immunotherapy via dendritic cells. Adv Exp Med Biol 2005;560:105-114.
2. Briseno CG, Murphy TL, Murphy KM. Complementary diversification of dendritic cells and innate lymphoid cells. Curr Opin Immunol 2014;29:69-78.
3.    Faure F, Jouve M, Lebhar-Peguillet I, Sadaka C, Sepulveda F, Lantz O, et al. Blood monocytes sample MelanA/MART1 antigen for long-lasting cross-presentation to CD8(+) T cells after differentiation into dendritic cells. Int J Cancer 2018;142:133-144.
4. Sallusto F, Lanzavecchia A. Efficient presentation of soluble antigen by cultured human dendritic cells is maintained by granulocyte/macrophage colony-stimulating factor plus interleukin 4 and downregulated by tumor necrosis factor alpha. J Exp Med 1994;179:1109-1118.
5. Brown D, Trowsdale J, Allen R. The LILR family: modulators of innate and adaptive immune pathways in health and disease. Tissue Antigens 2004;64:215-225.
6. Norman PJ, Carey BS, Stephens HAF, Vaughan RW. DNA sequence variation and molecular genotyping of natural killer leukocyte immunoglobulin-like receptor, LILRA3. Immunogenetics 2003;55:165-171.
7.    Torkar M, Haude A, Milne S, Beck S, Trowsdale J, Wilson MJ. Arrangement of the ILT gene cluster: a common null allele of the ILT6 gene results from a 6.7-kbp deletion. Eur J Immunol 2000;30:3655-3662.
8. Hirayasu K, Ohashi J, Tanaka H, Kashiwase K, Ogawa A, Takanashi M, et al. Evidence for natural selection on leukocyte immunoglobulin-like receptors for HLA class I in Northeast Asians. Am J Hum Genet 2008;82:1075-1083.
9.    Koch S, Goedde R, Nigmatova V, Epplen JT, Muller N, de Seze J, et al. Association of multiple sclerosis with ILT6 deficiency. Genes Immun 2005;6:445-447.
10.    Kabalak G, Dobberstein SB, Matthias T, Reuter S, The YH, Dorner T, et al. Association of immunoglobulin-like transcript 6 deficiency with Sjogren’s syndrome. Arthritis Rheum 2009;60:2923-2925.
11.    Ordonez D, Sanchez AJ, Martinez-Rodriguez JE, Cisneros E, Ramil E, Romo N, et al. Multiple sclerosis associates with LILRA3 deletion in Spanish patients. Genes Immun 2009;10:579-585.
12.    Du Y, Su Y, He J, Yang Y, Shi Y, Cui Y, et al. Impact of the leucocyte immunoglobulin-like receptor A3 (LILRA3) on susceptibility and subphenotypes of systemic lupus erythematosus and Sjogren’s syndrome. Ann Rheum Dis 2015;74:2070-2075.
13.    Du Y, Cui Y, Liu X, Hu F, Yang Y, Wu X, et al. Contribution of functional LILRA3, but not nonfunctional LILRA3, to sex bias in susceptibility and severity of anti-citrullinated protein antibody-positive rheumatoid arthritis. Arthritis Rheumatol 2014;66:822-830.
14.    Low HZ, Ahrenstorf G, Pommerenke C, Habermann N, Schughart K, Ordonez D, et al. TLR8 regulation of LILRA3 in monocytes is abrogated in human immunodeficiency virus infection and correlates to CD4 counts and virus loads. Retrovirology 2016;13:15-28.
15.    Chanput W, Mes JJ, Wichers HJ. THP-1 cell line: an in vitro cell model for immune modulation approach. Int Immunopharmacol 2014;23:37-45.
16.    Paglia P, Chiodoni C, Rodolfo M, Colombo MP. Murine dendritic cells loaded in vitro with soluble protein prime cytotoxic T lymphocytes against tumor antigen in vivo. J Exp Med 1996;183:317-322.
17.    Nersting J, Svenson M, Andersen V, Bendtzen K. Maturation of human dendritic cells by monocyte-conditioned medium is dependent upon trace amounts of lipopolysaccharide inducing tumour necrosis factor alpha. Immunol Lett 2003;89:59-65.
18.    Ho CS, Munster D, Pyke CM, Hart DN, Lopez JA. Spontaneous generation and survival of blood dendritic cells in mononuclear cell culture without exogenous cytokines. Blood 2002;99:2897-2904.
19.    Du Y, Sun F, Zhou M, Wu X, Sun W, Jiang Y, et al. The expression and clinical significance of different forms of LILRA3 in systemic lupus erythematosus. Clin Rheumatol 2019;38:3099-3107.
20.    Merad M, Sathe P, Helft J, Miller J, Mortha A. The dendritic cell lineage: ontogeny and function of dendritic cells and their subsets in the steady state and the inflamed setting. Annu Rev Immunol 2013;31:563-604.
21.    Fransen JH, Hilbrands LB, Jacobs CW, Adema GJ, Berden JH, Van der Vlag J. Both early and late apoptotic blebs are taken up by DC and induce IL-6 production. Autoimmunity 2009;42:325-327.
22.    Fransen JH, Hilbrands LB, Ruben J, Stoffels M, Adema GJ, van der Vlag J, et al. Mouse dendritic cells matured by ingestion of apoptotic blebs induce T cells to produce interleukin-17. Arthritis Rheum 2009;60:2304-2313.
23.    Anderson KJ, Allen RL. Regulation of T-cell immunity by leucocyte immunoglobulin-like receptors: innate immune receptors for self on antigen-presenting cells. Immunology 2009;127:8-17.
24.    Jackson SH, Yu CR, Mahdi RM, Ebong S, Egwuagu CE. Dendritic cell maturation requires STAT1 and is under feedback regulation by suppressors of cytokine signaling. J Immunol 2004;172:2307-2315.
25.    Pfeifer AC, Timmer J, Klingmuller U. Systems biology of JAK/STAT signalling. Essays Biochem 2008;45:109-120.
26.    Jackson AM, Mulcahy LA, Porte J, Franks HA, El Refaee M, Wang Q, et al. Role of mitogen-activated protein kinase and PI3K pathways in the regulation of IL-12-family cytokines in dendritic cells and the generation of T H-responses. Eur Cytokine Netw 2010;21:319-328.
Iranian Journal of Basic Medical Sciences
Volume 24, Issue 2
February 2021
Pages 196-202

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