All-trans retinoic acid increases NF-κB activity in PMA-stimulated THP-1 cells upon unmethylated CpG challenge by enhancing cell surface TLR9 expression

Q3 · BIOLOGY

Article

Author: Trinh, Tam-Anh ; Kim, Jae Young ; Hoang, Thi Xoan

An active metabolite of vitamin A, all-trans retinoic acid (ATRA), is known to exert immunomodulatory functions. This study investigates the possible immune potentiating effect of ATRA on NF-κB activity in human monocytic THP-1 cells after exposure to unmethylated CpG DNA ODN2006. We observed that challenge with ODN2006 significantly enhanced the NF-κB activity of PMA-differentiated THP-1 cells. ATRA synergistically enhanced NF-κB activity of cells, in a concentration- and time-dependent manner. The enhanced NF-κB activity of PMA-differentiated THP-1 cells after ODN2006 challenge was dependent on the RAR/RXR pathway. To determine the mechanism involved in increasing in the NF-κB activity of stimulated THP-1 cells, we examined the effects of PMA and ATRA on the expression of TLR9 (a receptor of ODN2006) in THP-1 cells. PMA treatment significantly enhanced both the intracellular and cell surface expression of TLR9, while ATRA alone showed no effect. However, ATRA synergistically enhanced the cell surface TLR9 expression of PMA-differentiated cells. To determine whether the ATRA-enhanced NF-κB activity is due to the enhanced cell surface TLR9 expression, we examined NF-κB activity after treatment with anti-TLR9 blocking antibody. Results revealed that the anti-TLR9 antibody treatment almost completely reverses the ATRA-enhanced NF-κB activity, suggesting that ATRA enhances NF-κB activity through upregulation of the cell surface TLR9 expression in PMA-differentiated and unmethylated CpG challenged THP-1 cells.

01 Feb 2017·Zhongguo ji sheng chong xue yu ji sheng chong bing za zhi = Chinese journal of parasitology & parasitic diseases

[The regulatory effect of dendritic cells on Th17 cell differentiation and function in mouse infected with Plasmodium yoelii].

Article

Author: Gong, Zi-lin ; Luo, Lan ; Su, Ju-xiang ; Zhang, Hui-ming ; Chen, Guang ; Liu, Lei ; Bi, Sheng ; Cai, Lian-shun ; Wang, Fang-fang

ObjectiveTo investigate the regulatory effect of dendritic cells (DCs) on Th17 cell differentiation and function during mouse infection with Plasmodium yoelii 17XL strain (Py17XL) and the underlying mechanisms.MethodsTwelve female BALB/c mice were randomly assigned into the infection group (Py17XL), the TLR4 blocking group (Py17XL + TLR4), TLR9 blocking group (Py17XL + TLR9), and TLR4 and TLR9 combined blocking group (Py17XL + TLR4+TLR9)(n=3 in each group). Mice in the Py17XL + TLR4 or the Py17XL + TLR9 group received intraperitoneal injection of 10 μg anti-TLR4 or 50 μg anti-TLR9 antibody (both 0.4 ml) to block DCs function at one day before infection. The Py17XL group received same volume of PBS. All groups were then given intraperitoneal injection of 1×10(6) red blood cells (RBCs) infected with Py17XL. The RBC infection rate was calculated on days 0, 3 and 5 after infection, and spleen cell suspension was prepared, in which the CD11c+TLR9+ and Th17 cells were counted by flow cytometry. The levels of IFN-γ and IL-10 in supernatant of spleen cell culture were determined by ELISA.ResultsFlow cytometry showed that DCs were successfully blocked. On day 5 after infection, 28%,29%, 31% and 16.3% mice showed parasitemia in the Py17XL group, the Py17XL + TLR4 group, the Py17XL + TLR9 group, and the Py17XL + TLR4 + TLR9 group, respectively, and on day 7, the proportions were 43.3%, 47.5%, 32.5% and 8%. Mice in the Py17XL group and the Py17XL + TLR4 group all died, while those in other groups began to die from day 6. There was a slow rise of parasitemia rate in the Py17XL + TLR9 group and the Py17XL + TLR4 + TLR9 group compared with the Py17XL group, with a significant extension of survival to days 11 and 15. Results of flow cytometry showed that the proportions of Th17 cells were 1.2% and 1.44% in the Py17XL + TLR9 group and the Py17XL + TLR4 + TLR9 group on day 5, both sighificantly decreased compared with the Py17XL group (1.9%)(P < 0.05, P < 0.01). ELISA revealed that the levels of IFN-γ and IL-10 on day 5 in the Py17XL + TLR4 + TLR9 group [(232.4 ± 15.5) pg/ml and(1791.2 ± 58.2) pg/ml, respectively] were significantly higher than those in the Py17XL group[(90.7 ± 50.1) pg/ml and (962.6 ± 409.0) pg/ml](P < 0.05, P < 0.01).ConclusionsThe differentiation and function of Th17 cells are regulated by DCs during Py17XL infection. Blockade of DCs decreases parasitemia and extends lifetime of mice. Further studies are needed to clarify the exact mechanisms.

Frontiers in ImmunologyQ2 · MEDICINE

Anti-TLR7 Antibody Protects Against Lupus Nephritis in NZBWF1 Mice by Targeting B Cells and Patrolling Monocytes

Q2 · MEDICINE

ArticleOA

Author: Yamaguchi, Kiyoshi ; Motoi, Yuji ; Furukawa, Yoichi ; Suzuki, Hitoshi ; Fukui, Ryutaro ; Tanaka, Reika ; Sato, Ryota ; Amano, Hirofumi ; Suzuki, Yusuke ; Kanno, Atsuo ; Murakami, Yusuke ; Tamura, Naoto ; Miyake, Kensuke ; Yamashita, Naomi

Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by autoantibody production and multiple organ damage. Toll-like receptor 7 (TLR7), an innate immune RNA sensor expressed in monocytes/macrophages, dendritic cells (DCs), and B cells, promotes disease progression. However, little is known about the cellular mechanisms through which TLR7 drives lupus nephritis. Here, we show that the anti-mouse TLR7 mAb, but not anti-TLR9 mAb, protected lupus-prone NZBWF1 mice from nephritis. The anti-TLR7 mAb reduced IgG deposition in glomeruli by inhibiting the production of autoantibodies to the RNA-associated antigens. We found a disease-associated increase in Ly6Clow patrolling monocytes that expressed high levels of TLR7 and had upregulated expression of lupus-associated IL-10, CD115, CD31, and TNFSF15 in NZBWF1 mice. Anti-TLR7 mAb abolished this lupus-associated increase in patrolling monocytes in the circulation, spleen, and glomeruli. These results suggested that TLR7 drives autoantibody production and lupus-associated monocytosis in NZBWF1 mice and, that anti-TLR7 mAb is a promising therapeutic tool targeting B cells and monocytes/macrophages.

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Indication	Highest Phase	Country/Location	Organization	Date
Diagnostic agents	Preclinical	US	BioLegend, Inc.	26 May 2023

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