All-trans retinoic acid (ATRA) reprograms human CIPN monocytes/macrophages ex vivo, reducing inflammation and boosting antioxidants
Background
Chemotherapy-induced peripheral neuropathy (CIPN) is a severe and common side effect of agents like paclitaxel and cisplatin, significantly impacting patient quality of life. Current treatments are often insufficient, leaving a critical gap in managing its debilitating symptoms. The pathophysiology of CIPN involves persistent inflammation and oxidative stress, leading to neuronal damage. All-trans retinoic acid (ATRA), known for its antioxidant and immunomodulatory properties, presents a promising avenue for modulating immune cell responses and potentially mitigating CIPN progression.
Study Design
Researchers isolated peripheral blood mononuclear cells (PBMCs) from eight patients diagnosed with CIPN. CD14⁺ monocytes were then purified using fluorescence-activated cell sorting. These monocytes were treated with various concentrations of ATRA. Cell viability and apoptosis were assessed using MTT and Annexin V-FITC/PI assays. Expression of inflammation-associated microRNAs was quantified via qRT-PCR. Cytokine levels and antioxidant enzyme activities (superoxide dismutase, catalase) were measured using ELISA. Monocytes were differentiated into macrophages with M-CSF, and their polarization was evaluated using CD86 (M1) and CD206 (M2) markers. Apoptosis-related proteins and inflammatory signaling markers were analyzed by flow cytometry.
Results
ATRA treatment significantly inhibited monocyte proliferation and induced apoptosis in the ex vivo human cells. The intervention increased anti-inflammatory microRNAs, specifically miR-144-5p and miR-125b, while simultaneously suppressing the pro-inflammatory miR-155. Furthermore, ATRA effectively reduced levels of pro-inflammatory cytokines and enhanced the production of anti-inflammatory mediators. A notable finding was the increased activity of antioxidant enzymes, including superoxide dismutase and catalase, indicating improved cellular defense against oxidative stress. Macrophage polarization was also favorably modulated: > ATRA promoted a shift towards the anti-inflammatory M2 phenotype, characterized by increased CD206 expression. This suggests a rebalancing of immune cell function. The study also observed ATRA's modulation of various apoptosis- and inflammation-related signaling proteins, reinforcing its multifaceted immunomodulatory effects.
Key Findings
- ATRA inhibited monocyte proliferation and induced apoptosis in CIPN patient cells.
- ATRA increased anti-inflammatory microRNAs (
miR-144-5p,miR-125b) and suppressed pro-inflammatorymiR-155. - ATRA reduced pro-inflammatory cytokine levels and enhanced anti-inflammatory mediator production.
- ATRA increased antioxidant enzyme activity (
superoxide dismutase,catalase). - ATRA promoted macrophage polarization towards the anti-inflammatory M2 phenotype.
Why It Matters
This ex vivo study provides compelling evidence that ATRA can rebalance immune cell function in CIPN, shifting monocytes and macrophages towards an anti-inflammatory and antioxidant profile. For individuals suffering from CIPN, this suggests a potential therapeutic strategy to mitigate nerve damage and alleviate symptoms by targeting underlying inflammation and oxidative stress. While still in the preclinical stage, these findings open the door for future in vivo studies and clinical trials to explore ATRA as an adjunct therapy. Integrating ATRA could potentially reduce the severity and progression of CIPN, offering a novel approach beyond current symptomatic management. The observed modulation of microRNAs and macrophage polarization highlights a sophisticated mechanism that could be leveraged for targeted interventions.
all-trans-retinoic-acid
cipn
chemotherapy-induced-peripheral-neuropathy
inflammation
macrophage-polarization
oxidative-stress