Genetically Engineered Macrophages Derived from iPSCs for Self-Regulating Delivery of Anti-Inflammatory Biologic Drugs

Figure 1

Depiction of the reprogrammed inflammatory signaling pathway in CRISPR-Cas9-engineered iMACs for the biologic Ccl2-sTNFR1 (1) and reporter Ccl2-luciferase (2) circuits. (a) TNF signaling through the TNFR type 1 receptor initiates a cascade leading to nuclear translocation and increased transcriptional activity of NF-κB, activating an inflammatory transcriptional program. (b) The Ccl2 promotor is then activated, which induces the expression of soluble TNF type 1 receptor (sTNFR1) in the biologic circuit (1) and luciferase in the reporter circuit (2). (c) Upon antagonism of TNF in the microenvironment, signal transduction through TNFR1 and the NF-κB inflammatory cascade is inhibited. (d) Expression of the sTNFR1 transgene decreases upon inhibition of NF-κB initiating inflammation.