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Fig. 1 | Journal of Neuroinflammation

Fig. 1

From: Temporal changes in macrophage phenotype after peripheral nerve injury

Fig. 1

IFNɣ and IL4 are key upstream regulators of macrophage gene expression in injured nerve. a Unsupervised hierarchical clustering on differential gene expression over time identified six clusters of genes. The PANTHER GO database overrepresentation test was performed. Cluster 1 was unclassified, but contained the macrophage alternative activation marker Retnla, which increased from days 5 to 14 (red). Cluster 2 was enriched for the common biological functions of coagulation, immune response, and cell communication and included genes Alox15, Jun, and Egr1. Cluster 3 was unclassified and included genes such as Nes and Clu. Cluster 4 was dominated by cell proliferation and cytokine receptor binding, and included Chi3l3, Arg1, Ccl2, Ccl7, and Il1a, which decreased from days 5 to 14 (blue). Cluster 5 was enriched for genes related to macrophage activation and response to IFNɣ, and included Nos2. This pro-inflammatory signature declined over time. The sixth cluster contained only Sct. Red— increased with time; blue—decreased with time. b Ingenuity pathway analysis identified key pathways including granulocyte and agranulocyte adhesion and diapedesis, angiogenesis, and dendritic cell maturation. c LPS, IFNγ, STAT3, and IL4 were identified as key upstream regulators of changes in macrophage gene expression. Gene expression was compared pairwise between three time points and 382 genes met the stringent differential expression (DE) cutoff in at least one time point comparison. Stringent cutoffs of FPKM > 5 and fold change > 2 were used. RNASeq was performed on sorted macrophages from BALB/cJ mice 5, 14, and 28 days after sciatic nerve transection and repair (n = 3/group). Further analysis of differentially expressed (DE) transcripts between time points (days 5 vs 14; days 14 vs 28) were analyzed for over-representation of biological functions, pathways, and networks using Downstream Effects Analysis to identify those biological processes and functions that are likely to be causally affected by up- and downregulated genes, using the bioinformatics software ingenuity pathways analysis (IPA)

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