The orphan nuclear receptor SHP acts as a negative regulator in inflammatory signaling triggered by Toll-like receptors

Abstract

The orphan nuclear receptor SHP (small heterodimer partner) is a transcriptional corepressor that regulates hepatic metabolic pathways. Here we identified a role for SHP as an intrinsic negative regulator of Toll-like receptor (TLR)-triggered inflammatory responses. SHP-deficient mice were more susceptible to endotoxin-induced sepsis. SHP had dual regulatory functions in a canonical transcription factor NF-κB signaling pathway, acting as both a repressor of transactivation of the NF-κB subunit p65 and an inhibitor of polyubiquitination of the adaptor TRAF6. SHP-mediated inhibition of signaling via the TLR was mimicked by macrophage-stimulating protein (MSP), a strong inducer of SHP expression, via an AMP-activated protein kinase-dependent signaling pathway. Our data identify a previously unrecognized role for SHP in the regulation of TLR signaling.

AMP-activated Kinase (AMPK) Promotes Innate Immunity and Antiviral Defense through Modulation of Stimulator of Interferon Genes (STING) Signaling

“…AMPK activators such as AICAR, metformin, and resveratrol, have been linked to antiinflammatory activities through inhibition of NF-B signaling (54 -56) and AMPK activation causes up-regulation of the negative regulatory protein Small Heterodimer Partner (also known as NR0B2) (57). From a clinical standpoint, AICAR may be able to mitigate allergy or other lung injuries by reducing airway inflammation (58,59) and it has also been shown to attenuate the severity of experimental autoimmune encephalitis in mouse models of multiple sclerosis (60,61).…”

Cellular and molecular regulation of innate inflammatory responses

“…In addition, a number of nuclear receptors, such as glucocorticoid receptor, 53 peroxisome proliferator-activated receptor gamma, 54 liver X receptor, 55 small heterodimer partner (SHP), 56 nuclear receptor subfamily 4, group A, members (NR4A1) 57 and (NR4A2) 58 inhibit TLR4-induced NF-κB downstream genes via inhibiting NF-κB activity and/or enhancing the NCoR/SMRT corepressor complex to limit inflammatory gene programs. NR4A1 enhances host resistance to lipopolysaccharide (LPS) sepsis in mice via inhibiting NF-κB binding on target gene promoter regions.…”

The Ron Receptor Tyrosine Kinase Regulates Macrophage Heterogeneity and Plays a Protective Role in Diet-Induced Obesity, Atherosclerosis, and Hepatosteatosis

“…NF-kB and Stat1 promote an inflammatory phenotype in macrophages by coordinately inducing inflammatory gene expression. Ron inhibits the activation of NF-kB in response to LPS by targeting the ubiquitination of TNFR-associated factor 6 and the nuclear localization of NF-kB (16,18,19). Ron also inhibits IFN-g-induced Stat1 phosphorylation, associated with the upregulation of the inhibitors of cytokine signaling, suppressor of cytokine signaling 1 and 3 (12,20).…”