Skip to main content
SpringerLink
Log in

TREM-2 mediates dendritic cell–induced NO to suppress Th17 activation and ameliorate chronic kidney diseases

  • Original Article
  • Published:
Journal of Molecular Medicine Aims and scope Submit manuscript

Abstract

Chronic kidney disease (CKD) is a global public health issue. CKD is caused by the infiltration of various myeloid cell types into renal tissue, resulting in renal fibrosis and tubular atrophy. Unilateral ureteral obstruction (UUO) surgery in mice is a model of CKD and characterized by high expression of the anti-inflammatory receptor, Triggering receptor expressed on myeloid cells 2 (TREM-2), on myeloid cells in affected kidneys. Here, we show that iNOS expression and nitric oxide (NO) induction were decreased in Trem-2−/− bone marrow-derived DCs (BMDCs) and in Trem-2 knockdown DC2.4 cells stimulated in vitro with LPS. The nitration of RORγt was decreased in T cells co-cultured with LPS-stimulated Trem-2−/− BMDCs, enhancing IL-17 production. UUO-treated Trem-2−/− mice displayed aggravated renal pathogenesis accompanied by greater neutrophil infiltration and enhanced Th17 cells differentiation, phenotypes that could be rescued by the administration of L-arginine (a biological precursor of NO). Our data identify a key mechanism underlying TREM-2-mediated NO to modulate the cellular crosstalk between dendritic cells, Th17, and neutrophils. Furthermore, we also reveal TREM-2 as a potential novel target for the development of anti-inflammatory drugs in CKD treatment.

Key messages

  • The expression of TREM-2 is increased in nephritis

  • TREM-2+ DCs maintain NO production to negatively regulate Th17 differentiation

  • The severe pathologies of nephritis can be rescued by L-arginine supplementation

Graphical Abstract

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6

Similar content being viewed by others

Availability of data and materials

Data and materials related to this study are available upon request.

References

  1. Eknoyan G, Lameire N, Barsoum R et al (2004) The burden of kidney disease: improving global outcomes. Kidney Int 66:1310–1314

    Article  PubMed  Google Scholar 

  2. Yatim KM, Lakkis FG (2015) A brief journey through the immune system. Clin J Am Soc Nephrol 10:1274–1281

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Tecklenborg J, Clayton D, Siebert S et al (2018) The role of the immune system in kidney disease. Clin Exp Immunol 192:142–150

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Nagler W (1973) Vertebral artery obstruction by hyperextension of the neck: report of three cases. Arch Phys Med Rehabil 54:237–240

    CAS  PubMed  Google Scholar 

  5. Dong X, Bachman LA, Miller MN et al (2008) Dendritic cells facilitate accumulation of IL-17 T cells in the kidney following acute renal obstruction. Kidney Int 74:1294–1309

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Kitamoto K, Machida Y, Uchida J et al (2009) Effects of liposome clodronate on renal leukocyte populations and renal fibrosis in murine obstructive nephropathy. J Pharmacol Sci 111:285–292

    Article  CAS  PubMed  Google Scholar 

  7. Daws MR, Lanier LL, Seaman WE et al (2001) Cloning and characterization of a novel mouse myeloid DAP12-associated receptor family. Eur J Immunol 31:783–791

    Article  CAS  PubMed  Google Scholar 

  8. Turnbull IR, Gilfillan S, Cella M et al (2006) Cutting edge: TREM-2 attenuates macrophage activation. J Immunol 177:3520–3524

    Article  CAS  PubMed  Google Scholar 

  9. Cella M, Buonsanti C, Strader C et al (2003) Impaired differentiation of osteoclasts in TREM-2-deficient individuals. J Exp Med 198:645–651

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Takahashi K, Rochford CD, Neumann H (2005) Clearance of apoptotic neurons without inflammation by microglial triggering receptor expressed on myeloid cells-2. J Exp Med 201:647–657

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. N’Diaye EN, Branda CS, Branda SS et al (2009) TREM-2 (triggering receptor expressed on myeloid cells 2) is a phagocytic receptor for bacteria. J Cell Biol 184:215–223

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Hamerman JA, Jarjoura JR, Humphrey MB et al (2006) Cutting edge: inhibition of TLR and FcR responses in macrophages by triggering receptor expressed on myeloid cells (TREM)-2 and DAP12. J Immunol 177:2051–2055

    Article  CAS  PubMed  Google Scholar 

  13. Li C, Zhao B, Lin C et al (2019) TREM2 inhibits inflammatory responses in mouse microglia by suppressing the PI3K/NF-kappaB signaling. Cell Biol Int 43:360–372

    Article  CAS  PubMed  Google Scholar 

  14. Di Virgilio F (2004) New pathways for reactive oxygen species generation in inflammation and potential novel pharmacological targets. Curr Pharm Des 10:1647–1652

    Article  PubMed  Google Scholar 

  15. Michel T, Feron O (1997) Nitric oxide synthases: which, where, how, and why? J Clin Invest 100:2146–2152

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Saini R, Singh S (2019) Inducible nitric oxide synthase: an asset to neutrophils. J Leukoc Biol 105:49–61

    Article  CAS  PubMed  Google Scholar 

  17. Ersoy Y, Ozerol E, Baysal O et al (2002) Serum nitrate and nitrite levels in patients with rheumatoid arthritis, ankylosing spondylitis, and osteoarthritis. Ann Rheum Dis 61:76–78

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Oudkerk Pool M, Bouma G, Visser JJ et al (1995) Serum nitrate levels in ulcerative colitis and Crohn′s disease. Scand J Gastroenterol 30:784–788

    Article  CAS  PubMed  Google Scholar 

  19. Nathan CF, Hibbs JB Jr (1991) Role of nitric oxide synthesis in macrophage antimicrobial activity. Curr Opin Immunol 3:65–70

    Article  CAS  PubMed  Google Scholar 

  20. Granger DN, Kubes P (1996) Nitric oxide as antiinflammatory agent. Methods Enzymol 269:434–442

    Article  CAS  PubMed  Google Scholar 

  21. Brune B, von Knethen A, Sandau KB (1999) Nitric oxide (NO): an effector of apoptosis. Cell Death Differ 6:969–975

    Article  CAS  PubMed  Google Scholar 

  22. Li J, Billiar TR (2000) The role of nitric oxide in apoptosis. Semin Perinatol 24:46–50

    Article  CAS  PubMed  Google Scholar 

  23. Niedbala W, Alves-Filho JC, Fukada SY et al (2011) Regulation of type 17 helper T-cell function by nitric oxide during inflammation. Proc Natl Acad Sci U S A 108:9220–9225

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Niedbala W, Besnard AG, Jiang HR et al (2013) Nitric oxide-induced regulatory T cells inhibit Th17 but not Th1 cell differentiation and function. J Immunol 191:164–170

    Article  CAS  PubMed  Google Scholar 

  25. Jianjun Y, Zhang R, Lu G et al (2013) T cell-derived inducible nitric oxide synthase switches off Th17 cell differentiation. J Exp Med 210:1447–1462

    Article  CAS  Google Scholar 

  26. Shen Z, Reznikoff G, Dranoff G et al (1997) Cloned dendritic cells can present exogenous antigens on both MHC class I and class II molecules. J Immunol 158:2723–2730

    CAS  PubMed  Google Scholar 

  27. Lo TH, Tseng KY, Tsao WS et al (2014) TREM-1 regulates macrophage polarization in ureteral obstruction. Kidney Int 86:1174–1186

    Article  CAS  PubMed  Google Scholar 

  28. Xu K, Wu N, Min Z et al (2020) Adoptive transfer of bone marrow-derived dendritic cells (BMDCs) alleviates OVA-induced allergic airway inflammation in asthmatic mice. Sci Rep 10:13915

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Napoli C, Ignarro LJ (2003) Nitric oxide-releasing drugs. Annu Rev Pharmacol Toxicol 43:97–123

    Article  CAS  PubMed  Google Scholar 

  30. Yang FC, Chiu PY, Chen Y et al (2019) TREM-1-dependent M1 macrophage polarization restores intestinal epithelium damaged by DSS-induced colitis by activating IL-22-producing innate lymphoid cells. J Biomed Sci 26:46

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  31. Csonka C, Pali T, Bencsik P et al (2015) Measurement of NO in biological samples. Br J Pharmacol 172:1620–1632

    Article  CAS  PubMed  Google Scholar 

  32. Tezuka H, Abe Y, Iwata M et al (2007) Regulation of IgA production by naturally occurring TNF/iNOS-producing dendritic cells. Nature 448:929–933

    Article  CAS  PubMed  Google Scholar 

  33. Tammaro A, Stroo I, Rampanelli E et al (2013) Role of TREM1-DAP12 in renal inflammation during obstructive nephropathy. PLoS ONE 8:e82498

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  34. Chung AC, Lan HY (2011) Chemokines in renal injury. J Am Soc Nephrol 22:802–809

    Article  CAS  PubMed  Google Scholar 

  35. Daley JM, Thomay AA, Connolly MD et al (2008) Use of Ly6G-specific monoclonal antibody to deplete neutrophils in mice. J Leukoc Biol 83:64–70

    Article  CAS  PubMed  Google Scholar 

  36. Tapmeier TT, Fearn A, Brown K et al (2010) Pivotal role of CD4+ T cells in renal fibrosis following ureteric obstruction. Kidney Int 78:351–362

    Article  CAS  PubMed  Google Scholar 

  37. Wang H, Wang J, Bai Y et al (2016) CD11c(+) CD8(+) T cells reduce renal fibrosis following ureteric obstruction by inducing fibroblast apoptosis. Int J Mol Sci 18(1):1

    Article  PubMed Central  CAS  Google Scholar 

  38. Pindjakova J, Hanley SA, Duffy MM et al (2012) Interleukin-1 accounts for intrarenal Th17 cell activation during ureteral obstruction. Kidney Int 81:379–390

    Article  CAS  PubMed  Google Scholar 

  39. Flannigan KL, Ngo VL, Geem D et al (2017) IL-17A-mediated neutrophil recruitment limits expansion of segmented filamentous bacteria. Mucosal Immunol 10:673–684

    Article  CAS  PubMed  Google Scholar 

  40. Miyajima A, Chen J, Poppas DP et al (2001) Role of nitric oxide in renal tubular apoptosis of unilateral ureteral obstruction. Kidney Int 59:1290–1303

    Article  CAS  PubMed  Google Scholar 

  41. Esplugues JV (2002) NO as a signalling molecule in the nervous system. Br J Pharmacol 135:1079–1095

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Ito K, Chen J, Vaughan ED Jr et al (2004) Dietary L-arginine supplementation improves the glomerular filtration rate and renal blood flow after 24 hours of unilateral ureteral obstruction in rats. J Urol 171:926–930

    Article  CAS  PubMed  Google Scholar 

  43. Bogdan C, Rollinghoff M, Diefenbach A (2000) The role of nitric oxide in innate immunity. Immunol Rev 173:17–26

    Article  CAS  PubMed  Google Scholar 

  44. Xiong H, Zhu C, Li F et al (2004) Inhibition of interleukin-12 p40 transcription and NF-kappaB activation by nitric oxide in murine macrophages and dendritic cells. J Biol Chem 279:10776–10783

    Article  CAS  PubMed  Google Scholar 

  45. Gupta KJ, Kolbert Z, Durner J et al (2020) Regulating the regulator: nitric oxide control of post-translational modifications. New Phytol 227:1319–1325

    Article  CAS  PubMed  Google Scholar 

  46. Zhai Q, Li F, Chen X et al (2017) Triggering receptor expressed on myeloid cells 2, a novel regulator of immunocyte phenotypes. Confers Neuroprotection by Relieving Neuroinflammation Anesthesiology 127:98–110

    CAS  PubMed  Google Scholar 

  47. Cantoni C, Bollman B, Licastro D et al (2015) TREM2 regulates microglial cell activation in response to demyelination in vivo. Acta Neuropathol 129:429–447

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Ito K, Chen J, Seshan SV et al (2005) Dietary arginine supplementation attenuates renal damage after relief of unilateral ureteral obstruction in rats. Kidney Int 68:515–528

    Article  CAS  PubMed  Google Scholar 

  49. Sun D, Wang Y, Liu C et al (2012) Effects of nitric oxide on renal interstitial fibrosis in rats with unilateral ureteral obstruction. Life Sci 90:900–909

    Article  CAS  PubMed  Google Scholar 

  50. Tirani SA, Pezeshki Z, Nematbakhsh M et al (2015) Effect of L-arginine and L-NAME on kidney tissue damage in rats after 24 h of bilateral ureteral obstruction. Int J Prev Med 6:60

    Article  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

We thank Dr. W. C. Yeh for his contribution in initiating the Trem-2-/- mouse project during his time at CFIBCR/UHN/Univ. Toronto in Toronto, Canada. We thank Dr. Hui-Chen Chen (China Medical University, Taichung, Taiwan) for providing DC2.4 cells. We thank Dr. Chi-Hung Lin (National Yang Ming Chiao Tung University, Taipei, Taiwan) for providing 293T cells.

Funding

This work was supported by grants to NJC and DCT from the Ministry of Science and Technology of Taiwan (MOST 109–2811-B-010–052, 107–2314-B-075–052, 108–2314-B-075–008, 109–2811-B-010–502) and grants to JLF (MOST 106–2321-B-075–001; 107–2321-B-075–001; 108–2321-B-075–001). PSO and TWM were supported by grants from the Canadian Institute of Health Research, the Leukemia Lymphoma Society, and the Terry Fox Cancer Research Foundation.

Author information

Authors and Affiliations

  1. Institute of Microbiology and Immunology, National Yang Ming Chiao Tung University, No. 155, Sec. 2, Linong St, Beitou District, Taipei, 11221, Taiwan

    Ching-Cheng Lin, Yun-Syuan Wu, Wei Huang, Wei-Chi Lo, Guan-Fu Liu, Wei-Chan Hsu & Nien-Jung Chen

  2. Department and Institute of Physiology, National Yang Ming Chiao Tung University, No. 155, Sec. 2, Linong St, Beitou District, Taipei, 11221, Taiwan

    Ti-Yung Chang & Der-Cherng Tarng

  3. Princess Margaret Cancer Centre, Ontario Cancer Institute, Toronto, ON, M5G 2C1, Canada

    Yong-Chen Lu, Pamela S. Ohashi & Tak W. Mak

  4. Current Contact Information: Department of Pathology and Winthrop P. Rockefeller Cancer Institute, University of Arkansas for Medical Sciences, Little Rock, AR, 72205, USA

    Yong-Chen Lu

  5. Department of Neurology, Neurological Institute, Taipei Veterans General Hospital, Taipei, 11217, Taiwan

    Jong-Ling Fuh

  6. Brain Research Center, National Yang Ming Chiao Tung University, Taipei, 11221, Taiwan

    Jong-Ling Fuh & Nien-Jung Chen

  7. Division of Nephrology, Department of Medicine, Taipei Veterans General Hospital, Taipei, 11217, Taiwan

    Der-Cherng Tarng

  8. Department of Microbiology and Immunology, School of Medicine and the Research and Development Center for Immunology, China Medical University, Taichung City, 406040, Taiwan, Republic of China

    Hui-Chen Chen

  9. Cancer Progression Research Center, National Yang Ming Chiao Tung University, Taipei, 11221, Taiwan

    Nien-Jung Chen

Authors
  1. Ching-Cheng Lin
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Ti-Yung Chang
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Yong-Chen Lu
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Yun-Syuan Wu
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Wei Huang
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Wei-Chi Lo
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Guan-Fu Liu
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Wei-Chan Hsu
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Pamela S. Ohashi
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Tak W. Mak
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Jong-Ling Fuh
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Hui-Chen Chen
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Der-Cherng Tarng
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. Nien-Jung Chen
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

Ching-Cheng Lin performed experiments, analyzed results, and drafted the manuscript. Ti-Yung Chang, Yun-Syuan Wu, Wei Huang, Wei-Chi Lo, Guan-Fu Liu, and Wei-Chan Hsu performed the experiments. Yong-Chen Lu, Pamela S. Ohashi, and Tak W. Mak established and provided the Trem-2−/− mouse model. Jong-Ling Fuh and Nien-Jung Chen identified the role of TREM-2 in iNOS induction in Alzheimer’s disease–related study. Hui-Chen Chen provided the DC2.4 cell line and made suggestions for the manuscript. Der-Cherng Tarng and Nien-Jung Chen designed experiments, analyzed results, interpreted findings, and wrote the final manuscript. All authors read and approved the final manuscript.

Corresponding authors

Correspondence to Der-Cherng Tarng or Nien-Jung Chen.

Ethics declarations

Ethics approval and consent to participate

All animal experiments were performed in accordance with the Institutional Animal Care and Use Committee Guidelines of National Yang Ming Chiao Tung University and carried out following the National Institutes of Health Guidelines for the Care and Use of Laboratory Animals (IACUC number: 1060436).

Consent for publication

Not applicable.

Competing interests

The authors declare no competing interests.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary Information

Below is the link to the electronic supplementary material.

Supplementary file1 (PDF 3423 KB)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Lin, CC., Chang, TY., Lu, YC. et al. TREM-2 mediates dendritic cell–induced NO to suppress Th17 activation and ameliorate chronic kidney diseases. J Mol Med 100, 917–931 (2022). https://doi.org/10.1007/s00109-022-02201-7

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00109-022-02201-7

Keywords

Search

Navigation