ERK Signaling Is Essential for Macrophage Development

Richardson, Edward T.; Shukla, Supriya; Nagy, Nancy; Boom, W. Henry; Beck, Rose; Zhou, Lan; Landreth, Gary E.; Harding, Clifford V.

doi:10.1371/journal.pone.0140064

Cited by 67 publications

(54 citation statements)

References 34 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Additionally, there was significant inhibition of phosphorylated ERK1/2 in groups treated with DNTs. Recent studies have shown that the MAPK pathway plays an important role in macrophage activation and proliferation . The apparent role of SHP2 inhibitors in regulating ERK inhibition has been previously studied in cancer cells, but it has been relatively unexplored in macrophages.…”

mentioning

confidence: 99%

CSF1R‐ and SHP2‐Inhibitor‐Loaded Nanoparticles Enhance Cytotoxic Activity and Phagocytosis in Tumor‐Associated Macrophages

et al. 2019

View full text Add to dashboard Cite

Immune modulation of macrophages has emerged as an attractive approach for anti‐cancer therapy. However, there are two main challenges in successfully utilizing macrophages for immunotherapy. First, macrophage colony stimulating factor (MCSF) secreted by cancer cells binds to colony stimulating factor 1 receptor (CSF1‐R) on macrophages and in turn activates the downstream signaling pathway responsible for polarization of tumor‐associated macrophages (TAMs) to immunosuppressive M2 phenotype. Second, ligation of signal regulatory protein α (SIRPα) expressed on myeloid cells to CD47, a transmembrane protein overexpressed on cancer cells, activates the Src homology region 2 (SH2) domain ‐phosphatases SHP‐1 and SHP‐2 in macrophages. This results in activation of “eat‐me‐not” signaling pathway and inhibition of phagocytosis. Here, it is reported that self‐assembled dual‐inhibitor‐loaded nanoparticles (DNTs) target M2 macrophages and simultaneously inhibit CSF1R and SHP2 pathways. This results in efficient repolarization of M2 macrophages to an active M1 phenotype, and superior phagocytic capabilities as compared to individual drug treatments. Furthermore, suboptimal dose administration of DNTs in highly aggressive breast cancer and melanoma mouse models show enhanced anti‐tumor efficacy without any toxicity. These studies demonstrate that the concurrent inhibition of CSF1‐R and SHP2 signaling pathways for macrophage activation and phagocytosis enhancement could be an effective strategy for macrophage‐based immunotherapy.

show abstract

mentioning

confidence: 99%

CSF1R‐ and SHP2‐Inhibitor‐Loaded Nanoparticles Enhance Cytotoxic Activity and Phagocytosis in Tumor‐Associated Macrophages

et al. 2019

View full text Add to dashboard Cite

show abstract

“…These include STAT1 (signal transducer and activator of transcription 1-alpha/beta) – a critical mediator of the pro-inflammatory response of macrophages to LPS [84] – and the transcription factors ATF3 , a known inducer of STAT1 [85], and SPI1/PU.1 , which is essential for macrophage differentiation [86]. Also in the network are the tyrosine kinase LYN , which is activated alongside STAT1 in response to IL5 (a key mediator of eosinophil activation [87]), and the adaptor protein GRB2 , which facilitates the activation of ERK by tyrosine kinases [88] ( ERK signalling is essential to macrophage development [89]). In addition, the network contained SOCS3 , a negative regulator of cytokine signalling that inhibits the nuclear translocation of STAT1 in response to IFN stimulation [90], with this stimulation a key constituent of classical macrophage activation [91].…”

Section: Resultsmentioning

confidence: 99%

Combination of novel and public RNA-seq datasets to generate an mRNA expression atlas for the domestic chicken

Bush

Freem

MacCallum

et al. 2018

Preprint

View full text Add to dashboard Cite

“…5a), suggesting that CSF1/CSF1R signaling up-regulates Caspase-3 cleavage in the AGM region at E10.5. ERK1/2 and PI3K-Akt pathways are reportedly activated during myelopoiesis through CSF1/CSF1R signaling [51,52], while both ERK1/2 and Akt were not phosphorylated (Fig. 5a).…”

Section: Discussionmentioning

confidence: 99%

Embryonic Intra-Aortic Clusters Undergo Myeloid Differentiation Mediated by Mesonephros-Derived CSF1 in Mouse

Sasaki

Tanaka

Kulkeaw

et al. 2016

Stem Cell Rev and Rep

View full text Add to dashboard Cite

The aorta-gonad-mesonephros (AGM) region contains intra-aortic clusters (IACs) thought to have acquired hematopoietic stem cell (HSC) potential in vertebrate embryos. To assess extrinsic regulation of IACs in the AGM region, we employed mouse embryos harboring a Sall1-GFP reporter gene, which allows identification of mesonephros cells based on GFP expression. Analysis of AGM region tissue sections confirmed mesonephros GFP expression. Mesonephric cells sorted at E10.5 expressed mRNA encoding Csf1, a hematopoietic cytokine, and corresponding protein, based on real-time PCR and immunocytochemistry, respectively. Further analysis indicated that some IACs express the CSF1 receptor, CSF1R. Expression of Cebpa and Irf8 mRNAs was higher in CSF1R-positive IACs, whereas that of Cebpε and Gfi1 mRNAs was lower relative to CSF1R-negative IACs, suggesting that CSF1/CSF1R signaling functions in IAC myeloid differentiation by modulating expression of these transcription factors. Colony formation assays using CSF1R-positive IACs revealed increased numbers of myeloid colonies in the presence of CSF1. Analysis using an intra-cellular signaling array indicated the greatest fold increase of Cleaved Caspase-3 in AGM cells in the presence of CSF1. Immunohistochemistry revealed that Cleaved Caspase-3 is primarily expressed in IACs in the AGM region, and incubation of IACs with CSF1 up-regulated Cleaved Caspase-3. Overall, our findings suggest that CSF1 secreted from mesonephros accelerates IAC myeloid differentiation in the AGM region, possibly via Caspase-3 cleavage.

show abstract

ERK Signaling Is Essential for Macrophage Development

Cited by 67 publications

References 34 publications

CSF1R‐ and SHP2‐Inhibitor‐Loaded Nanoparticles Enhance Cytotoxic Activity and Phagocytosis in Tumor‐Associated Macrophages

CSF1R‐ and SHP2‐Inhibitor‐Loaded Nanoparticles Enhance Cytotoxic Activity and Phagocytosis in Tumor‐Associated Macrophages

Combination of novel and public RNA-seq datasets to generate an mRNA expression atlas for the domestic chicken

Embryonic Intra-Aortic Clusters Undergo Myeloid Differentiation Mediated by Mesonephros-Derived CSF1 in Mouse

Contact Info

Product

Resources

About