Erdr1 orchestrates macrophage polarization and determines cell fate via dynamic interplay with YAP1 and Mid1

Erythroid differentiation regulator 1 (Erdr1) is a stress-induced, widely distributed, extremely conserved secreted factor found in both humans and mice. Erdr1 is highly linked with the Hippo-YAP1 signaling. Initially identified as an inducer of hemoglobin synthesis, it has emerged as a multifunctional protein, especially in immune cells. Although Erdr1 has been implicated in T cells and NK cell function, its role in macrophage remains unclear. This study aims to explore the function and mechanism of Erdr1 in IL-1β production in macrophages. Data manifest Erdr1 could play an inhibition role in IL-1β production, which also has been reported by previous research. What significance is we discovered Erdr1 can promote IL-1β production which is associated with Erdr1 dose and cell density. We observed that Erdr1 was inhibited in pro-inflammatory (M1) macrophages but was upregulated in anti-inflammatory (M2) macrophages compared to naive macrophages. We hypothesized that Erdr1 dual drives and modulates IL-1β production by binding with distinct adaptors via concentration change. Mechanistically, we demonstrated that Erdr1 dual regulates IL-1β production by dynamic interaction with YAP1 and Mid1 by distinct domains. Erdr1-YAP1 interplay mediates macrophage M2 polarization by promoting an anti-inflammatory response, enhancing catabolic metabolism, and leading to sterile cell death. Whereas, Erdr1-Mid1 interplay mediates macrophage M1 polarization by initiating a pro-inflammatory response, facilitating anabolic metabolism, and causing inflammatory cell death. This study highlights Erdr1 orchestrates macrophage polarization and determines cell date by regulating YAP1 through non-classical Hippo pathway.