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

Abstract

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-κB activity and suppressing aberrant cytokine production. Nur77 directly associates with p65 to block its binding to the κB element. However, this function of Nur77 is countered by the LPS-activated p38α phosphorylation of Nur77. Dampening the interaction between Nur77 and p38α 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-p38α interaction by targeting the ligand-binding domain of Nur77 and restored the suppression of the hyperinflammatory response through Nur77 inhibition of NF-κB. This study associates the nuclear receptor with immune homeostasis and implicates a new therapeutic strategy to treat hyperinflammatory responses by targeting a p38α substrate to modulate p38α-regulated functions.

Histone acetylation regulates orphan nuclear receptor NR4A1 expression in hypercholesterolaemia

“…Ismail et al [46] and You et al [34] reported that, in ECs, NR4A1 inhibits NF-κB activation through up-regulation of IκBα (inhibitor of NF-κB α), by binding to an NR4A1-binding element in the IκBα promoter [34,46]. Another mechanism by which NR4A1 influences NF-κB activation is through direct interaction with the p65 subunit of NF-κB, and blocking p65 binding to its κB element to attenuate the production of pro-inflammatory cytokines [48,49]. These studies suggest that the orphan nuclear receptor NR4A1 is induced by inflammatory stimuli, and exerts an anti-inflammatory effects by suppressing NF-κB activity.…”

Transcription factor Nr4a1 couples sympathetic and inflammatory cues in CNS-recruited macrophages to limit neuroinflammation

“…Both pro- and anti-inflammatory roles for Nr4a1 have been described in various functional settings, including its modulation of the NF-κB pathway 49,50 . Another Nr4a member, Nr4a2 (Nurr1), expressed in microglia and astrocytes, was shown to mediate neuroprotection by recruiting the CoREST transrepressor to promoters of NF-κB target genes 51 .…”

Adenosine Modulates NR4A Orphan Nuclear Receptors To Attenuate Hyperinflammatory Responses in Monocytic Cells

“…NR4A1 promotes and controls the early monocyte proinflammatory responses, which is required for the initiation of inflammatory resolution and subsequent monocyte-derived, macrophage-dependent reparative/healing phase. Similar molecular mechanisms are used in controlling immune homeostasis in LPS-induced sepsis to permit NR4A1-mediated control of hyperinflammatory responses (47). From such studies it is becoming evident that the local environment influences the differentiation stage/ function of immune cells, thus determining the cell-specific contribution NR4A receptors play in guiding the magnitude of inflammatory responses and outcomes (41).…”

“…In addition, altering the expression level of these constitutively active receptors may be a feasible approach to modulate NR4A target genes in a cell-specific manner. The in vivo therapeutic potential of targeting NR4A/NF-kB interactions to control immune homeostasis has recently been uncovered (47). A chemical compound n-pentyl 2-[3,5-dihydroxy-2-(1-nonanoyl)-phenyl]acetate targets the ligand-binding domain of NR4A1 and prevents phosphorylation of NR4A1 by TLR-activated p38a.…”