Abstract
Following re-exposure to lipopolysaccharide (LPS), macrophages exhibit an immunosuppressive state known as LPS tolerance, which is characterized by repressed proinflammatory cytokine production. LPS-induced tolerance in macrophages is mediated in part by epigenetic changes. Carboplatin, an anticancer chemotherapeutic drug, exerts its effect by inhibiting DNA replication and transcription, as well as through epigenetic modifications. Through an unbiased screen, we found that carboplatin rescued TNF-α and IL-6 production in LPS-tolerant macrophages. Transcriptomic analysis and gene set enrichment analyses revealed that p53 was one of the most significantly upregulated hallmarks in both LPS-primed and LPS-tolerant macrophages in the presence of carboplatin, while E2F and G2/M were the most negatively regulated hallmarks. Heterochromatin protein 1 (HP1-α), which is associated with gene silencing, was significantly reduced in carboplatin-treated LPS-tolerant macrophages at the mRNA and protein levels. Dynamic changes in the mRNA level of genes encoding H3K9me3 methyltransferases, setdb2, kdm4d, and suv39h1 were induced in the presence of carboplatin in LPS-tolerant macrophages. Taken together, we provide evidence that carboplatin treatment interferes with proinflammatory cytokine production during the acute LPS response and LPS tolerance in macrophages, possibly via H3K9me3 modification.
Highlights
Carboplatin, an antineoplastic drug, is a platinum-based agent classified as an alkylating agent[1]
We tested the procedure to induce LPS tolerance in bone marrow-derived macrophages (BMDMs); we monitored the levels of the proinflammatory cytokines TNF-α and IL-6 in BMDMs that were primed with LPS (1° LPS; 100 ng/ml) without carboplatin for 24 h and compared them with BMDMs receiving 1° LPS followed by re-exposure to LPS (2° LPS; 10 ng/ml) for another 3 h (Fig. 1A, upper panel)
We reported the effect of a platinum-containing anticancer chemotherapy drug, carboplatin, on the response of macrophages to LPS and LPS tolerance
Summary
Carboplatin, an antineoplastic drug, is a platinum-based agent classified as an alkylating agent[1]. Emerging evidence suggests that innate immune cells (e.g., macrophages, monocytes, and natural killer cells) are able to develop memory-like responses to previous encounters against bacterial lipopolysaccharides (LPS)[16]. Based on our detailed study, we proposed that carboplatin might be able to interfere with epigenetic controls, especially alterations in the H3K9 hallmark, and thereby alters responses in LPS-induced tolerant macrophages. This knowledge will allow for a better understanding of the effect of antitumor drugs on innate immune memory, which may have implications for the clinical care of chemotherapy-treated cancer patients
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