The epigenetic state of IL-4-polarized macrophages enables inflammatory cistromic expansion and extended synergistic response to TLR ligands

Czimmerer, Zsolt; Halász, László; Dániel, Bence; Varga, Zsofia; Bene, Krisztian; Domokos, Apolka; Hoeksema, Marten A.; Shen, Zeyang; Berger, Wilhelm K.; Cseh, Timea; Jambrovics, Karoly; Kolostyák, Zsuzsanna; Fenyvesi, Ferenc; Váradi, Judit; Póliska, Szilárd; Hajas, György; Szatmári, István; Glass, Christopher K.; Bácsi, Attila; Nagy, László

doi:10.1016/j.immuni.2022.10.004

Cited by 34 publications

(31 citation statements)

References 78 publications

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“…Moreover, CX3CR1 hi Ly6C int F4/80 + I-A + /I-E + macrophages were discovered as a new osteoclast precursor, and disease-specific macrophages involved in the pathogenesis of allergy, fibrosis, and metabolic syndrome were also found despite being categorized as a conventional M2 macrophages (42)(43)(44)(45)(46). Similar to our experimental condition, it can be speculated that unique macrophages were induced by LPS and IL-4, in the lung with the asthma with bacterial infection (9,47).…”

Section: Discussionsupporting

confidence: 76%

Induction of unique macrophage subset by simultaneous stimulation with LPS and IL-4

et al. 2023

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Macrophages manifest as various subtypes that play diverse and important roles in immunosurveillance and the maintenance of immunological homeostasis in various tissues. Many in vitro studies divide macrophages into two broad groups: M1 macrophages induced by lipopolysaccharide (LPS), and M2 macrophages induced by interleukin 4 (IL-4). However, considering the complex and diverse microenvironment in vivo, the concept of M1 and M2 is not enough to explain diversity of macrophages. In this study, we analyzed the functions of macrophages induced by simultaneous stimulation with LPS and IL-4 (termed LPS/IL-4-induced macrophages). LPS/IL-4-induced macrophages were a homogeneous population showing a mixture of the characteristics of M1 and M2 macrophages. In LPS/IL-4-induced macrophages, expression of cell-surface M1 markers (I-Ab) was higher than in M1 macrophages, but lower expression of iNOS, and expression of M1-associated genes (Tnfα and Il12p40) were decreased in comparison to expression in M1 macrophages. Conversely, expression of the cell-surface M2 marker CD206 was lower on LPS/IL-4-induced macrophages than on M2 macrophages and expression of M2-associated genes (Arg1, Chi3l3, and Fizz1) varied, with Arg1 being greater than, Fizz1 being lower than, and Chi3l3 being comparable to that in M2 macrophages. Glycolysis-dependent phagocytic activity of LPS/IL-4-induced macrophages was strongly enhanced as was that of M1 macrophages; however, the energy metabolism of LPS/IL-4-induced macrophages, such as activation state of glycolytic and oxidative phosphorylation, was quite different from that of M1 or M2 macrophages. These results indicate that the macrophages induced by LPS and IL-4 had unique properties.

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Section: Discussionsupporting

confidence: 76%

Induction of unique macrophage subset by simultaneous stimulation with LPS and IL-4

et al. 2023

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“…However, any of the mechanisms should be affected by the different expression levels and functions of TFs and coregulators, including KDMs and KMTs, in either signaling context. M1 and M2 signaling pathways crosstalk with each other ( 16 , 75 ) and must be further addressed by integrating synergistic and antagonistic coregulator networks such as those identified here.…”

Section: Discussionmentioning

confidence: 99%

Antagonistic action of GPS2 and KDM1A at enhancers governs alternative macrophage activation by interleukin 4

Huang

Efthymiadou

Liang

et al. 2023

Nucleic Acids Research

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The Th2 cytokine interleukin 4 (IL4) promotes macrophage differentiation into alternative subtypes and plays important roles in physiology, in metabolic and inflammatory diseases, in cancer and in tissue regeneration. While the regulatory transcription factor networks governing IL4 signaling are already well-characterized, it is currently less understood which transcriptional coregulators are involved and how they operate mechanistically. In this study, we discover that G protein pathway suppressor 2 (GPS2), a core subunit of the HDAC3 corepressor complex assembled by SMRT and NCOR, represses IL4-dependent enhancer activation in mouse macrophages. Our genome-wide and gene-specific characterization revealed that, instead of directly repressing STAT6, chromatin-bound GPS2 cooperates with SMRT and NCOR to antagonize enhancer activation by lysine demethylase 1A (KDM1A, LSD1). Mechanistically, corepressor depletion increased KDM1A recruitment to enhancers linked to IL4-induced genes, accompanied by demethylation of the repressive histone marks H3K9me2/3 without affecting H3K4me1/2, the classic KDM1A substrates for demethylation in other cellular contexts. This in turn caused enhancer and gene activation already in the absence of IL4/STAT6 and sensitized the STAT6-dependent IL4 responsiveness of macrophages. Thus, our work identified with the antagonistic action of a GPS2-containing corepressor complex and the lysine demethylase KDM1A a hitherto unknown epigenetic corepressor-coactivator switching mechanism that governs alternative macrophage activation.

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“…Interestingly, CytoSig data lacked many hallmark effects of Th1 and Th2 modulators. For example, the potent inhibitory effect of the Th2 cytokine IL-4 on IFNg, TNFa and IL-1b was missing, as was its ability to induce CCL22 and CCL24 15,[18][19][20] (Fig 3e). In fact, nELISA detected many more interactions in PBMCs than CytoSig (449 vs 137).…”

Section: Nelisa Reveals Cytokine Interaction Insights Beyond Transcri...mentioning

confidence: 99%

nELISA: A high-throughput, high-plex platform enables quantitative profiling of the secretome

Dagher

Ongo²,

Robichaud³

et al. 2023

Preprint

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We present the nELISA, a miniaturised, high-throughput, and high-fidelity protein profiling platform. DNA oligonucleotides are used to pre-colocalize antibody pairs on spectrally encoded microparticles and perform displacement-mediated detection while ensuring spatial separation between non-cognate antibody pairs. Read-out is performed cost-efficiently and at high-throughput using flow cytometry. We assembled an inflammatory panel of 191 targets that were multiplexed without cross-reactivity or impact to performance vs 1-plex signals, with sensitivities as low as 0.1pg/mL and measurements across the platform spanning 8 orders of magnitude. We then performed a large-scale PBMC secretome screen, with cytokines as both perturbagens and read-outs, measuring 7,392 samples and generating ~1.5M protein datapoints in under a week, a significant advance in throughput compared to other highly multiplexed immunoassays. We uncovered 447 significant cytokine responses, including multiple putatively novel cytokine responses, that were conserved across donors and stimulation conditions. We also validated its use in phenotypic screening, and proposed applications for the nELISA in drug discovery.

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The epigenetic state of IL-4-polarized macrophages enables inflammatory cistromic expansion and extended synergistic response to TLR ligands

Cited by 34 publications

References 78 publications

Induction of unique macrophage subset by simultaneous stimulation with LPS and IL-4

Induction of unique macrophage subset by simultaneous stimulation with LPS and IL-4

Antagonistic action of GPS2 and KDM1A at enhancers governs alternative macrophage activation by interleukin 4

nELISA: A high-throughput, high-plex platform enables quantitative profiling of the secretome

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