Fig. 6.

Anti-inflammatory cytokines IL-35 and IL-10 block LPC-induced innate immune activation, but not immune memory in HAECs. LPC could induce innate immune transdifferentiation in HAECs, which is characterized by enhanced expression of adhesion molecules, cytokines, chemokines, danger-associated molecular pattern (DAMP) receptors, costimulatory molecules, and MHC class II. This process is characterized by two steps: In the first step, LPC induce metabolic reprogramming, including upregulation of glycolysis, mevalonate enzymes, and acetyl-CoA generation, leading to chromatin remodeling in the genomic regions encoding innate immune signature genes and innate immune memory. In the second step, LPC-induced mtROS are responsible for the recruitment of pro-inflammatory transcription factors, leading to innate immune activation. While IL-35 and IL-10 could suppress LPC-induced innate immune activation via inhibiting mtROS, they could not suppress LPC-induced metabolic reprogramming and trained innate immune memory response.