Erdr1 orchestrates macrophage polarization and determines cell fate via dynamic interaction 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. 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 precise function of Erdr1 in IL-1β production in macrophages and uncover the underlying mechanisms. 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 has the capacity to promote IL-1β production which is associated with Erdr1 dose and cell density. We observed that Erdr1 has distinct expression patterns in pro-inflammatory (M1) and anti-inflammatory (M2) macrophages compared to naive macrophages. We hypothesized that Erdr1 dual modulates IL-1β production by binding with distinct adaptors via concentration change. Mechanistically, we demonstrated that Erdr1 has dynamic interaction with YAP1 and Mid1 by distinct domains. These intricate interplays not only govern the dynamic regulation of IL-1β production but also mediate macrophage functional and metabolic reprogramming and determine cell fate. This study highlights that Erdr1 orchestrates macrophage polarization by regulating YAP1 through the non-classical Hippo pathway.