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Epigenomic and Functional Convergence Between Glucocorticoid- and IL4-Driven Macrophage Programming (ChIP-Seq)

ABSTRACT: Macrophage polarization is implicated in acute and chronic inflammatory settings, and central to diseases such as obesity, atherosclerosis and cancer. However, the transcription programs driving macrophage polarization are only partially known. Macrophage phenotypes exist on a spectrum, with anti-inflammatory (M2-like) and pro-inflammatory (M1-like) states viewed as polar opposite and relatively stable phenotype. The main driver of the M2-like program in response to IL4 is the Krüppel-like factor 4(KLF4), which uses transcriptional coregulator GRIP1 as a co-activator. Coincidentally, glucocorticoid hormone (GC)-activated GC receptor (GR) also induces the M2-like state, and GRIP1 is a well-known co-factor of GR. We are investigating if GRIP1 facilitates transcriptional and phenotypic convergence of the M2-like state via the GR and KLF4-regulated pathways. Using RNA-seq on bone marrow-derived macrophages (BMDMs) from WT and GRIP1-cKO mice, we have shown that GR and KLF4-regulated pathways share common and distinct transcriptomes. A lot of the key M2 genes are GRIP1-dependent, and some key pro-inflammatory targets need GRIP1 for suppression in the M2–like state. Similarly, H3K27ac ChIP and ATAC-seq, which profile active and open chromatin regions respectively, revealed both specific and shared enhancers for these two pathways in the M2-like state. GR recruitment to the genomic binding sites was shown to be strictly GC-specific, whereas GRIP1 is recruited in both signal-specific and combinatorial manner. It is plausible that GRIP1 facilitates the binding of GR and KLF4 to the shared enhancers, thus leading to overlapping changes in gene expression. At the cellular level, GC- and particularly IL4-polarized GRIP1-cKO BMDMs exhibit reduced phagocytosis, an M2-characteristic activity, compared to the WT. Furthermore, in vivo, in the acute inflammatory setting of DSS-induced colitis, GRIP1-cKO mice exhibit greater colonic inflammation and tissue destruction, and fail to up-regulate M2 genes to the same degree as the WT. GRIP1 is therefore a crucial regulator of macrophage polarization to the anti-inflammatory state. The specific contribution of GRIP1 to the shared transcriptional phenotype is currently being assessed.

ORGANISM(S): Mus musculus

PROVIDER: GSE247447 | GEO | 2024/09/03

REPOSITORIES: GEO

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Project description:Macrophage polarization is implicated in acute and chronic inflammatory settings, and central to diseases such as obesity, atherosclerosis and cancer. However, the transcription programs driving macrophage polarization are only partially known. Macrophage phenotypes exist on a spectrum, with anti-inflammatory (M2-like) and pro-inflammatory (M1-like) states viewed as polar opposite and relatively stable phenotype. The main driver of the M2-like program in response to IL4 is the Krüppel-like factor 4(KLF4), which uses transcriptional coregulator GRIP1 as a co-activator. Coincidentally, glucocorticoid hormone (GC)-activated GC receptor (GR) also induces the M2-like state, and GRIP1 is a well-known co-factor of GR. We are investigating if GRIP1 facilitates transcriptional and phenotypic convergence of the M2-like state via the GR and KLF4-regulated pathways. Using RNA-seq on bone marrow-derived macrophages (BMDMs) from WT and GRIP1-cKO mice, we have shown that GR and KLF4-regulated pathways share common and distinct transcriptomes. A lot of the key M2 genes are GRIP1-dependent, and some key pro-inflammatory targets need GRIP1 for suppression in the M2–like state. Similarly, H3K27ac ChIP and ATAC-seq, which profile active and open chromatin regions respectively, revealed both specific and shared enhancers for these two pathways in the M2-like state. GR recruitment to the genomic binding sites was shown to be strictly GC-specific, whereas GRIP1 is recruited in both signal-specific and combinatorial manner. It is plausible that GRIP1 facilitates the binding of GR and KLF4 to the shared enhancers, thus leading to overlapping changes in gene expression. At the cellular level, GC- and particularly IL4-polarized GRIP1-cKO BMDMs exhibit reduced phagocytosis, an M2-characteristic activity, compared to the WT. Furthermore, in vivo, in the acute inflammatory setting of DSS-induced colitis, GRIP1-cKO mice exhibit greater colonic inflammation and tissue destruction, and fail to up-regulate M2 genes to the same degree as the WT. GRIP1 is therefore a crucial regulator of macrophage polarization to the anti-inflammatory state. The specific contribution of GRIP1 to the shared transcriptional phenotype is currently being assessed.

Project description:Inflammation is the natural defensive response of the immune system to an injury or infection and is regulated by small molecule mediators triggering different phases of the inflammatory process. In particular, lipid mediators (LM) and cytokines exhibit crucial regulatory functions in the progression and resolution of inflammation. Macrophages play a central role in this process and can adopt distinct phenotypes with specialized functions depending on their microenvironment: inflammatory M1 macrophages drive inflammation by the release of pro-inflammatory cytokines and LMs, like prostaglandins (PG) and leukotrienes (LT), while resolving M2 macrophages promote inflammation resolution and tissue regeneration by production of anti-inflammatory cytokines and specialized pro resolving mediators (SPM). Aging is associated with chronic and unresolved, low-grade inflammation (“inflammaging”) and aging-related dysfunction of macrophages in the resolution of inflammation and tissue maintenance has been reported. Yet, the underlying molecular mechanisms and functional consequences of latter processes remain poorly understood. Here, we show that polarization of peritoneal macrophages (PM) from geriatric mice towards an M2-like phenotype is impaired versus adult mice, resulting in aberrant LM formation and cytokine release. In PMs isolated from adult mice (PM-A) we observed a shift in LM formation from PGs and LTs to SPMs already after 4 h of polarization towards M2 with interleukin (IL) 4. In contrast, PMs from geriatric mice (PM-G) produced mainly LTs and PGs upon polarization. This pattern persists over the course of 48 h of polarization. Proteomic profiling revealed that polarization of PM A towards M2 yields a more distinct phenotype, clearly separated from M1, when compared to PM-G. We observed similar aging-related changes in the lipidome and cytokine profile of spleen, lung and liver tissue from mice. Hence, we hypothesize that during aging macrophage polarization towards M2 is impaired, which in turn drives chronic inflammation and disturbs tissue maintenance. By combining state-of-the art lipidomic and proteomic profiling we aim to uncover new molecular targets for pharmaceutical interventions to improve therapeutic strategies for elderly patients with chronic inflammatory diseases.

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Epigenomic and Functional Convergence Between Glucocorticoid- and IL4-Driven Macrophage Programming (ChIP-Seq)

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