The chemotherapeutic drug carboplatin affects macrophage responses to LPS and LPS tolerance via epigenetic modifications

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.

ELOVL6 is associated with immunosuppression in lung adenocarcinoma through bioinformatics analysis

“…The E2F signaling pathway and the G2M checkpoint are also involved in platinum resistance. [54,55] In this study, GSEA analysis showed that ELOVL6 is involved in the E2F signaling pathway, G2M checkpoint, MTORC1 signaling pathway, apoptosis, PI3K-AKT-MTOR signaling pathway and P53 signaling pathway, suggesting that ELOVL6 may play an important role in regulating various cellular functions such as cell cycle, proliferation, metabolism, and survival. [56–59] Among them, the E2F signaling pathway, G2M checkpoint, PI3K-AKT-MTOR signaling pathway and P53 signaling pathway are involved in tumor resistance to EGFR-TKI and platinum-based drugs, respectively.…”

“…[56–59] Among them, the E2F signaling pathway, G2M checkpoint, PI3K-AKT-MTOR signaling pathway and P53 signaling pathway are involved in tumor resistance to EGFR-TKI and platinum-based drugs, respectively. [54,55,60–63] This suggests that up-regulation of ELOVL6 may mediate the development of associated drug resistance through the signaling pathways described above.…”

Prolonged Inhibition of the MEK1/2-ERK Signaling Axis Primes Interleukin-1 Beta Expression through Histone 3 Lysine 9 Demethylation in Murine Macrophages

“…The tolerance-reversing and priming effects of MEK1/2-ERK inhibition are reminiscent of the effects induced by ultra-low doses of LPS [37][38][39], BCG vaccine [40], C. albicans [41] and its cell wall component β-glucan [4,42], oxidized low-density lipoprotein (ox-LDL) [43,44], and the antineoplastic agent known as carboplatin [45]. These stimuli commonly reverse LPS tolerance and/or train/prime macrophages through epigenetic reprogramming.…”

Epigenetic memory contributing to the pathogenesis of AKI-to-CKD transition

“…Toll-like receptors (TLRs) exposed to bacterial endotoxin, such as LPS, induce the transient silencing of a subset of genes, including those encoding proinflammatory mediators, and exhibit a transient immunosuppressive state upon recurrent stimulation with LPS (“LPS tolerance”). This is one of the most important mechanisms that protects the host from dysregulated inflammation ( Foster et al, 2007 ; López-Collazo and del Fresno, 2013 ; Boonmee et al, 2021 ). Foster et al showed that several hundred genes, including those encoding antimicrobial effectors, induced by the initial exposure to LPS stimulation, exhibit enhanced expression upon subsequent LPS stimulation.…”