Machine Learning Identifies Signatures of Macrophage Reactivity and Tolerance
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE203423 | GEO | 2022/05/20
REPOSITORIES: GEO
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Project description:Background: Macrophage polarization programs, commonly referred to as âclassicalâ and âalternativeâ activation, are widely considered as distinct states that are exclusive of one another, and are associated with different functions such as inflammation and wound healing, respectively. In a number of disease contexts, such as traumatic brain injury (TBI), macrophage polarization influences the extent of pathogenesis, and efforts are underway to eliminate pathogenic subsets. However, previous studies have not distinguished whether the simultaneous presence of both classical and alternative activation signatures represents the admixture of differentially polarized macrophages, or if they have adopted a unique state characterized by components of both classical and alternative activation. Results: We analyzed the polarization of individual macrophages responding to TBI using single-cell RNA sequencing. Analysis of signature polarization genes revealed diverse activation states, including M(IL4), M(IL10), and M(LPS, IFNγ). However, the expression of a given polarization marker was no more likely than at random to predict simultaneous expression or repression of markers of another polarization program within the same cell, suggesting a lack of exclusivity in macrophage polarization states in vivo in TBI. Also unexpectedly, individual TBI macrophages simultaneously expressed high levels of signature polarization genes across two or three different polarization states, and in several distinct and seemingly incompatible combinations. Conclusions: Single-cell gene expression profiling demonstrated that monocytic macrophages in TBI are not comprised of distinctly polarized subsets, but are uniquely and broadly activated. TBI macrophage activation in vivo is deeply complex, with individual cells concurrently adopting both inflammatory and reparative features. These data provide physiologically relevant evidence that the early macrophage response to TBI is comprised of novel activation states that are discordant with the current paradigm of macrophage polarizationâa key consideration for therapeutic modulation. Monocyte derived macrophages were isolated from the ipsilateral hemisphere of mouse brains one day following traumatic brain injury elicited by control cortical impact in C57BL/6 adult male mice. Single-cells were isolated and processed for RNA sequencing using a Fluidigm C1 integrated fluidic circuit chip. 45 biological replicates were analyzed.
2016-05-17 | E-GEOD-79510 | biostudies-arrayexpress
Project description:Background: Macrophage polarization programs, commonly referred to as “classical” and “alternative” activation, are widely considered as distinct states that are exclusive of one another, and are associated with different functions such as inflammation and wound healing, respectively. In a number of disease contexts, such as traumatic brain injury (TBI), macrophage polarization influences the extent of pathogenesis, and efforts are underway to eliminate pathogenic subsets. However, previous studies have not distinguished whether the simultaneous presence of both classical and alternative activation signatures represents the admixture of differentially polarized macrophages, or if they have adopted a unique state characterized by components of both classical and alternative activation. Results: We analyzed the polarization of individual macrophages responding to TBI using single-cell RNA sequencing. Analysis of signature polarization genes revealed diverse activation states, including M(IL4), M(IL10), and M(LPS, IFNγ). However, the expression of a given polarization marker was no more likely than at random to predict simultaneous expression or repression of markers of another polarization program within the same cell, suggesting a lack of exclusivity in macrophage polarization states in vivo in TBI. Also unexpectedly, individual TBI macrophages simultaneously expressed high levels of signature polarization genes across two or three different polarization states, and in several distinct and seemingly incompatible combinations. Conclusions: Single-cell gene expression profiling demonstrated that monocytic macrophages in TBI are not comprised of distinctly polarized subsets, but are uniquely and broadly activated. TBI macrophage activation in vivo is deeply complex, with individual cells concurrently adopting both inflammatory and reparative features. These data provide physiologically relevant evidence that the early macrophage response to TBI is comprised of novel activation states that are discordant with the current paradigm of macrophage polarization—a key consideration for therapeutic modulation.
2016-05-17 | GSE79510 | GEO
Project description:Pluripotency is highly dynamic and progresses through a continuum of pluripotent stem-cell states. The two states that bookend the pluripotency continuum, naïve and primed, are well characterized, but our understanding of the intermediate states and transitions between them remain incomplete. Here, we dissect the dynamics of pluripotent state transitions underlying pre- to post-implantation epiblast differentiation. Through comprehensive mapping of the proteome, phosphoproteome, transcriptome, and epigenome of embryonic stem cells transitioning from naïve to primed pluripotency, we find that rapid, acute, and widespread changes to the phosphoproteome precede ordered changes to the epigenome, transcriptome, and proteome. Reconstruction of kinase-substrate networks reveals signaling cascades, dynamics, and crosstalk. Distinct waves of global proteomic changes mark discrete phases of pluripotency, with cell state-specific surface markers tracking pluripotent state transitions. Our data provide new insights into the multi-layered control of the phased progression of pluripotency and a foundation for modeling mechanisms regulating pluripotent state transitions (www.stemcellatlasorg).
2019-05-07 | PXD010621 | Pride
Project description:We describe a distinct macrophage population, whose presence in the liver during homoeostasis depends on recruitment signals mediated by the chemokine receptor CCR2. The identified polarization state of this population closely resembles that induced in co-culture experiments, where hepatocytes are reducing the availability of TGFb to macrophages. Accordingly, disruption of TGFb signal transduction in macrophages phenocopies the influence of hepatocytes on macrophage polarization.
2022-12-31 | E-MTAB-11727 | biostudies-arrayexpress
Project description:Obesity-associated insulin resistance is characterized by a state of chronic, low-grade inflammation that is associated with the accumulation of M1 proinflammatory macrophages in adipose tissue. Although different evidence explains the mechanisms linking the expansion of adipose tissue and adipose tissue macrophage (ATM) polarization, in the current study we investigated the concept of lipid-induced toxicity as the pathogenic link that could explain the trigger of this response. We addressed this question using isolated ATMs and adipocytes from genetic and diet-induced murine models of obesity. Through transcriptomic and lipidomic analysis, we created a model integrating transcript and lipid species networks simultaneously occurring in adipocytes and ATMs and their reversibility by thiazolidinedione treatment. We show that polarization of ATMs is associated with lipid accumulation and the consequent formation of foam cell–like cells in adipose tissue. Our study reveals that early stages of adipose tissue expansion are characterized by M2-polarized ATMs and that progressive lipid accumulation within ATMs heralds the M1 polarization, a macrophage phenotype associated with severe obesity and insulin resistance. Furthermore, rosiglitazone treatment, which promotes redistribution of lipids toward adipocytes and extends the M2 ATM polarization state, prevents the lipid alterations associated with M1 ATM polarization. Our data indicate that the M1 ATM polarization in obesity might be a macrophage-specific manifestation of a more general lipotoxic pathogenic mechanism. This indicates that strategies to optimize fat deposition and repartitioning toward adipocytes might improve insulin sensitivity by preventing ATM lipotoxicity and M1 polarization. 15 samples; 2 genotypes and 2 time points
2012-03-22 | E-GEOD-36669 | biostudies-arrayexpress
Project description:Macrophage polarization between the M2 (repair, pro-tumorigenic) and M1 (inflammatory) phenotypes is seen as a continuum of states. The detailed transcriptional events and signals downstream of CSF-1R that contribute to amplification of the M2 phenotype and suppression of the M1 phenotype are largely unknown. Macrophage CSF-1R pTyr-721 signaling promotes cell motility and enhancement of tumor cell invasion in vitro. Combining analysis of cellular systems for CSF-1R gain-of-function and loss-of-function with bioinformatic analysis of the macrophage CSF-1R pTyr-721-regulated transcriptome, we uncovered miR-21 as a downstream molecular switch controlling macrophage activation and identified ERK1/2 and NF-κB as CSF-1R pTyr-721-regulated signaling nodes. We show that CSF-1R pTyr-721 signaling suppresses the proinflammatory phenotype, predominantly by induction of miR-21. Profiling of the miR-21-regulated mRNAs revealed that 80% of the CSF-1-regulated canonical miR-21 targets are pro-inflammatory molecules. Additionally, miR-21 positively regulates M2 marker expression. Moreover, miR-21 feeds back to positively regulate its own expression and to limit CSF-1R-mediated activation of ERK1/2 and NF-κB. Consistent with an anti-inflammatory role of miRNA-21, intraperitoneal injection of mice with a miRNA-21 inhibitor increases the recruitment of inflammatory monocytes and enhances the peritoneal monocyte/macrophage response to lipopolysaccharide (LPS). These results identify the macrophage miR-21 network as a novel target for controlling macrophage polarization.
2014-10-23 | GSE62630 | GEO
Project description:This model is based on:
Computational Modeling of the Crosstalk Between Macrophage Polarization and Tumor Cell Plasticity in the Tumor Microenvironment.
Abstract:
Tumor microenvironments contain multiple cell types interacting among one another via different signaling pathways. Furthermore, both cancer cells and different immune cells can display phenotypic plasticity in response to these communicating signals, thereby leading to complex spatiotemporal patterns that can impact therapeutic response. Here, we investigate the crosstalk between cancer cells and macrophages in a tumor microenvironment through in silico (computational) co-culture models. In particular, we investigate how macrophages of different polarization (M1 vs. M2) can interact with epithelial-mesenchymal plasticity of cancer cells, and conversely, how cancer cells exhibiting different phenotypes (epithelial vs. mesenchymal) can influence the polarization of macrophages. Based on interactions documented in the literature, an interaction network of cancer cells and macrophages is constructed. The steady states of the network are then analyzed. Various interactions were removed or added into the constructed-network to test the functions of those interactions. Also, parameters in the mathematical models were varied to explore their effects on the steady states of the network. In general, the interactions between cancer cells and macrophages can give rise to multiple stable steady-states for a given set of parameters and each steady state is stable against perturbations. Importantly, we show that the system can often reach one type of stable steady states where cancer cells go extinct. Our results may help inform efficient therapeutic strategies.
2019-09-23 | MODEL1909230002 | BioModels
Project description:Machine Learning Identifies Signatures of Macrophage Reactivity and Tolerance
| PRJNA839943 | ENA
Project description:In response to microenvironmental signals macrophages undergo different activation, indicated as classic/M1 and alternative/M2 polarization. C-Myc transcription factor could be an essential player in M2 polarization. Functional relevance of c-Myc in M2 macrophage biology is investigated by evaluating the effect of 100-58F4, on the transcriptional profile induced on human macrophages by IL-4. Human monocytes were obtained from normal donor buffy coats by two-step gradient centrifugation using Ficoll (Biochrom) and Percoll (Amersham). Non-adherent cells were discarded, and the purified monocytes were incubated for 7 days in RPMI 1640 (Biochom) supplemented with 10% FCS (HyClone) and 100 ng/mL M-CSF to obtain resting macrophages. Macrophage polarization was obtained by removing the culture medium and culturing cells in RPMI 1640 supplemented with 10% FCS and 100 ng/mL LPS plus 20 ng/mL IFN-gamma (M1 polarization) or 20 ng/mL IL-4 (M2 polarization) for 24 h. When needed, chemical inhibitors were added with IL-4.
2011-09-15 | E-GEOD-32164 | biostudies-arrayexpress
Project description:Intracellular bacterial pathogens can exhibit large heterogeneity in growth rate inside host cells with major consequences for the infection outcome. If and how the host responds to this heterogeneity remains poorly understood. Here, we combined a fluorescent reporter of bacterial cell division with single-cell RNA-seq analysis to study the macrophage response to different intracellular states of the model pathogen Salmonella enterica serovar Typhimurium. The transcriptomes of individual infected macrophages revealed a spectrum of functional host response states to dividing and non-dividing bacteria. Intriguingly, macrophages harboring non-dividing Salmonella display hallmarks of the pro-inflammatory M1 polarization state and differ little from bystander cells, suggesting that non-dividing bacteria evade recognition by intracellular immune receptors. By contrast, macrophages containing dividing bacteria have turned into an anti-inflammatory, M2-like state, as if fast-growing intracellular Salmonella overcome host defense by reprogramming macrophage polarization. Additionally, our clustering approach reveals intermediate host functional states between these extremes. Altogether our data suggest that gene expression variability in infected host cells shapes different cellular environments, some of which may favor a growth arrest of Salmonella facilitating immune evasion and the establishment of a long-term niche; while others allow Salmonella to escape intracellular antimicrobial activity and proliferate.
2016-09-14 | GSE79363 | GEO