Impeding the interaction between Nur77 and p38 reduces LPS-induced inflammation

Sepsis, a hyperinflammatory response that can result in multiple organ dysfunctions, is a leading cause of mortality from infection. Here, we show that orphan nuclear receptor Nur77 (also known as TR3) can enhance resistance to lipopolysaccharide (LPS)-induced sepsis in mice by inhibiting NF-kappa B activity and suppressing aberrant cytokine production. Nur77 directly associates with p65 to block its binding to the kappa B element. However, this function of Nur77 is countered by the LPS-activated p38 alpha phosphorylation of Nur77. Dampening the interaction between Nur77 and p38 alpha would favor Nur77 suppression of the hyperinflammatory response. A compound, n-pentyl 2-[3,5-dihydroxy-2-(1-nonanoyl) phenyl]acetate, screened from a Nur77-biased library, blocked the Nur77-p38 alpha interaction by targeting the ligand-binding domain of Nur77 and restored the suppression of the hyperinflammatory response through Nur77 inhibition of NF-kappa B. This study associates the nuclear receptor with immune homeostasis and implicates a new therapeutic strategy to treat hyperinflammatory responses by targeting a p38 alpha substrate to modulate p38 alpha-regulated functions.