Abstract
RAR-related orphan receptor γ (RORγ) is a nuclear receptor that plays an essential role in the development of T helper 17 (Th17) cells of the adaptive immune system. The NLRP3 inflammasome is a component of the innate immune system that processes interleukin (IL)-1β into a mature cytokine. Elevated activity of the NLRP3 inflammasome contributes to the progression of an array of inflammatory diseases. Bone marrow-derived macrophages (BMDMs) isolated from RORγ-null mice displayed reduced capacity to secrete IL-1β, and they also displayed a reduction in Nlrp3 and Il1b gene expression. Examination of the promoters of the Il1b and Nlrp3 genes revealed multiple putative ROR response elements (ROREs) that were occupied by RORγ. RORγ inverse agonists were effective inhibitors of the inflammasome. RORγ inverse agonists suppressed lipopolysaccharide (LPS)/ATP-stimulated IL-1β secretion and expression of Il1b and Nlrp3 in BMDMs. Additionally, the ability of the RORγ inverse agonists to suppress IL-1β secretion was lost in Nlrp3-null macrophages. The potential for targeting the NLRP3 inflammasome in vivo using RORγ inverse agonists was examined in two models: LPS-induced sepsis and fulminant hepatitis. Pharmacological inhibition of RORγ activity reduced plasma IL-1β as well as IL-1β production by peritoneal macrophages in a model of LPS-induced sepsis. Additionally, RORγ inverse agonists reduced mortality in an LPS/d-galactosamine-induced fulminant hepatitis mouse model. These results illustrate a major role for RORγ in regulation of innate immunity via modulation of NLRP3 inflammasome activity. Furthermore, these data suggest that inhibiting the NLRP3 inflammasome with RORγ inverse agonists may be an effective method to treat NLRP3-associated diseases.
Highlights
RAR-related orphan receptor ␥ (ROR␥) is a nuclear receptor that plays an essential role in the development of T helper 17 (Th17) cells of the adaptive immune system
ROR␥ is required for normal NLRP3 inflammasome activity in macrophages
Given that ROR␥ often functions in a reciprocal manner to REV-ERB, we performed a similar experiment in Bone marrow– derived macrophages (BMDMs) from ROR␥-null mice
Summary
We recently demonstrated that the nuclear receptor REV-ERB␣ plays a role in regulation of the NLRP3 inflammasome [15]. In undifferentiated M0 BMDMs, we observed that Nlrp gene expression was reduced following LPS treatment in the ROR␥-null cells, but Il1b expression was not changed (Fig. 1A). Treatment with SR1555 decreased NLRP3 and IL1B gene expression in human cells, suggesting that ROR␥ regulates this pathway in humans as well as mice (Fig. S2) These data clearly suggest that targeting ROR␥ with pharmacological agents may be an effective method to inhibit NLRP3 inflammasome activity. Expression of Nlrp and Il1b was significantly reduced in the livers from mice treated with either SR1555 or SR2211 relative to the vehicle-treated mice These data clearly indicate that ROR␥ inverse agonists are protective in the mouse model of FH and suggest that at least one clear mechanism underlying this protection is inhibition of NLRP3 inflammasome activity
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