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

Ching-Cheng Lin1, Ti-Yung Chang2, Yong-Chen Lu3,4

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

Journal of Molecular Medicine (Berlin, Germany)
|May 9, 2022
PubMed

Insights

Triggering receptor expressed on myeloid cells 2 (TREM-2) on dendritic cells regulates nitric oxide (NO) production, impacting kidney disease. Supplementing L-arginine can rescue severe nephritis pathologies.

Area of Science:

  • Immunology
  • Nephrology
  • Cell Biology

Background:

  • Chronic kidney disease (CKD) is a significant global health concern.
  • CKD pathogenesis involves myeloid cell infiltration, leading to renal fibrosis and tubular atrophy.
  • Triggering receptor expressed on myeloid cells 2 (TREM-2) is upregulated on myeloid cells in kidney disease models.

Purpose of the Study:

  • To investigate the role of TREM-2 in regulating nitric oxide (NO) production by myeloid cells.
  • To elucidate the mechanism by which TREM-2 influences T helper 17 (Th17) cell differentiation and kidney inflammation.
  • To explore TREM-2 as a potential therapeutic target for CKD.

Main Methods:

  • Utilized unilateral ureteral obstruction (UUO) mouse model of CKD.
  • Assessed iNOS and NO production in TREM-2 deficient (Trem-2-/-) bone marrow-derived dendritic cells (BMDCs) and knockdown cells.
  • Analyzed RORγt nitration and IL-17 production in co-cultured T cells.
  • Evaluated renal pathology, neutrophil infiltration, and Th17 cell differentiation in UUO-treated Trem-2-/- mice.
  • Investigated the therapeutic effect of L-arginine supplementation.

Main Results:

  • TREM-2 deficiency reduced iNOS expression and NO induction in dendritic cells.
  • Reduced nitration of RORγt in T cells co-cultured with TREM-2 deficient dendritic cells led to enhanced IL-17 production.
  • UUO-treated Trem-2-/- mice showed exacerbated renal pathogenesis, increased neutrophil infiltration, and enhanced Th17 differentiation.
  • L-arginine administration rescued the aggravated renal pathology in Trem-2-/- mice.

Conclusions:

  • TREM-2 plays a crucial role in maintaining NO production by dendritic cells, which negatively regulates Th17 differentiation.
  • TREM-2 mediates cellular crosstalk between dendritic cells, Th17 cells, and neutrophils in the context of kidney injury.
  • TREM-2 represents a potential therapeutic target for anti-inflammatory strategies in CKD treatment.
Keywords:
Dendritic cellsNitric oxideTREM-2Th17UUO

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