Ex vivo modulation of monocyte/macrophage phenotypes by all-trans retinoic acid in chemotherapy-induced peripheral neuropathy.

BACKGROUND

Chemotherapy-induced peripheral neuropathy (CIPN) is a common and debilitating complication associated with chemotherapeutic agents such as paclitaxel, oxaliplatin, and cisplatin. Persistent inflammation and oxidative stress are key contributors to neuronal damage in CIPN. All-trans retinoic acid (ATRA) possesses antioxidant and immunomodulatory properties, suggesting potential therapeutic value in modulating immune cell responses in CIPN.

METHODS

Peripheral blood mononuclear cells (PBMCs) were isolated from peripheral blood of eight patients with CIPN, and CD14⁺ monocytes were purified using fluorescence-activated cell sorting. Monocytes were treated with different concentrations of ATRA, and cell viability and apoptosis were evaluated using MTT and Annexin V-FITC/PI assays. Expression of inflammation-associated microRNAs was measured using qRT-PCR. Cytokine levels and antioxidant enzyme activities (superoxide dismutase and catalase) were assessed using ELISA. Monocytes were differentiated into macrophages using M-CSF, and macrophage polarization was evaluated using CD86 (M1) and CD206 (M2) markers. Additionally, apoptosis-related proteins and inflammatory signaling markers were analyzed by flow cytometry.

RESULTS

ATRA inhibited monocyte proliferation and induced apoptosis. Treatment increased anti-inflammatory microRNAs (miR-144-5p and miR-125b) while suppressing pro-inflammatory miR-155. ATRA reduced pro-inflammatory cytokine levels, enhanced anti-inflammatory mediator production, and increased antioxidant enzyme activity. Furthermore, ATRA promoted macrophage polarization toward the anti-inflammatory M2 phenotype and modulated apoptosis- and inflammation-related signaling proteins.

CONCLUSIONS

ATRA regulates inflammation-associated microRNAs, reduces pro-inflammatory cytokine expression, enhances antioxidant defenses, and promotes M2 macrophage polarization. These findings suggest that ATRA can shift monocyte and macrophage function toward a potentially protective, anti-inflammatory phenotype, contributing to the development of future therapeutic strategies for CIPN.