巨噬细胞（MΦs）可以保护多发性骨髓瘤（MM）细胞免受化疗引起的凋亡，并且白细胞介素-10（IL-10）在MM微环境中常常升高。然而，IL-10在MΦ引起肿瘤化疗抵抗中的作用尚未明确。本研究中，利用骨髓源性MΦs处理了IL-10（IL10-MΦs），并评估了IL10-MΦ引起的MM化疗抵抗。结果显示，IL-10促进了MΦ介导的MM化疗抵抗。此外，IL-10处理增加了MΦ中的脂质积累和脂肪酸β-氧化。机制上，IL-10增加了MΦ中脂肪酸结合蛋白5（FABP5）的表达，并且靶向FABP5抑制了IL10-MΦ引起的MM化疗抵抗，并增强了体内化疗的疗效。抑制FABP5降低了IL10-MΦs中肌苷磷酸羧酯转移酶1A（CPT1A）的表达。此外，抑制CPT1A在IL10-MΦs中降低了IL10-MΦ引起的MM化疗抵抗。过氧化物酶体增殖物活化受体γ（PPARγ）是FABP5信号传导的上游。在IL10-MΦs中抑制PPARγ降低了IL10-MΦ引起的MM化疗抵抗。综上所述，我们的研究表明，IL-10通过FABP5信号传导增强了MΦ介导的MM化疗抵抗，而靶向FABP5具有重要的临床意义。版权所有 © 2023作者。由Elsevier B.V.出版，保留所有权利。

Macrophages (MΦs) protect multiple myeloma (MM) cells from chemotherapy-induced apoptosis, and interleukin-10 (IL-10) is frequently elevated in the MM microenvironment. However, the role of IL-10 in MΦ-induced tumor chemotherapy resistance has not yet been clarified. In the present study, bone marrow-derived MΦs were treated with IL-10 (IL10-MΦs), and IL10-MΦ-induced MM chemotherapy resistance was evaluated. IL-10 promoted MΦ-mediated resistance to MM chemotherapy. In addition, IL-10 treatment increased lipid accumulation and fatty acid β-oxidation in MΦs. Mechanistically, IL-10 increased fatty acid binding protein 5 (FABP5) expression in MΦs, and targeting FABP5 decreased MM chemotherapy resistance induced by IL10-MΦs in vitro and enhanced chemotherapeutic efficacy in vivo. Inhibition of FABP5 decreased the expression of Carnitine Palmitoyltransferase 1A (CPT1A) in IL10-MΦs. In addition, inhibition of CPT1A in IL10-MΦs decreased IL10-MΦ-mediated MM chemotherapy resistance. Peroxisome proliferator-activated receptor γ (PPARγ) is upstream of FABP5 signaling. Inhibition of PPARγ in IL10-MΦs decreased IL10-MΦ-mediated MM chemotherapy resistance in vitro. Collectively, our work indicates that IL-10 enhances MΦ-mediated MM chemotherapy resistance via FABP5 signaling and targeting FABP5 has potentially important clinical implications.Copyright © 2023 The Author(s). Published by Elsevier B.V. All rights reserved.