Endocrinol Metab.  2016 Mar;31(1):17-24. 10.3803/EnM.2016.31.1.17.

Small Heterodimer Partner and Innate Immune Regulation

• Yuk JM
• Jin HS
• Jo EK

• KMID: 2169687
• DOI: http://doi.org/10.3803/EnM.2016.31.1.17

Abstract

The nuclear receptor superfamily consists of the steroid and non-steroid hormone receptors and the orphan nuclear receptors. Small heterodimer partner (SHP) is an orphan family nuclear receptor that plays an essential role in the regulation of glucose and cholesterol metabolism. Recent studies reported a previously unidentified role for SHP in the regulation of innate immunity and inflammation. The innate immune system has a critical function in the initial response against a variety of microbial and danger signals. Activation of the innate immune response results in the induction of inflammatory cytokines and chemokines to promote anti-microbial effects. An excessive or uncontrolled inflammatory response is potentially harmful to the host, and can cause tissue damage or pathological threat. Therefore, the innate immune response should be tightly regulated to enhance host defense while preventing unwanted immune pathologic responses. In this review, we discuss recent studies showing that SHP is involved in the negative regulation of toll-like receptor-induced and NLRP3 (NACHT, LRR and PYD domains-containing protein 3)-mediated inflammatory responses in innate immune cells. Understanding the function of SHP in innate immune cells will allow us to prevent or modulate acute and chronic inflammation processes in cases where dysregulated innate immune activation results in damage to normal tissues.

Keyword

SHP orphan nuclear receptor; Immunity, innate; Social control, formal; Inflammation; Toll-like receptors; Inflammasomes

MeSH Terms

Chemokines
Child
Child, Orphaned
Cholesterol
Cytokines
Glucose
Humans
Immune System
Immunity, Innate
Inflammasomes
Inflammation
Metabolism
Orphan Nuclear Receptors
Social Control, Formal
Toll-Like Receptors
Chemokines
Cholesterol
Cytokines
Glucose
Inflammasomes
Orphan Nuclear Receptors
Toll-Like Receptors

Figure

• 

  Fig. 1 Roles of the orphan nuclear receptor small heterodimer partner (SHP) in the toll-like receptor 4 (TLR4)-mediated inflammatory response and NLRP3 (NACHT, LRR and PYD domains-containing protein 3) inflammasome activity. The orphan nuclear receptor SHP plays an important role in the negative regulation of lipopolysaccharide (LPS)-meditated inflammation and NLRP3 inflammasome activation. First, TLR4 engagement strongly acts to generate proinflammatory cytokines including tumor necrosis factor α (TNF-α), interleukin 6 (IL-6), IL-1β, and IL-12p40 through TNF receptor-associated factor 6 (TRAF6) ubiquitination and nuclear factor κB (NF-κB) p65 nuclear translocation. Moreover, the generation of mitochondrial reactive oxygen species (ROS) in macrophages is enhanced during LPS stimulation, which is closely associated with activation of the inflammatory response. The mitochondrial anion carrier protein uncoupling protein 2 (UCP2) is an essential component of mitochondrial ROS and inflammation modulation. Our previous studies indicated that endogenous SHP inhibits the TLR4-induced upregulation of proinflammatory responses through the modulation of TRAF6 polyubiquitination and UCP2 expression. Second, inflammasome activation results in the maturation of pro-IL-1β and pro-IL-18 and the secretion of these mature cytokines into the extracellular environment. SHP deficiency causes enhanced secretion of mature IL-1β and IL-18. On the other hand, overexpression of SHP effectively attenuates NLRP3 activation and secretion of IL-1β and IL-18 through direct interaction with NLRP3 protein. Third, treatment with fenofibrate or macrophage-stimulating factor (MSP) activates SHP gene expression through liver kinase B1 (LKB1)-dependent AMP-activated protein kinase activation and recruitment of upstream stimulatory factor-1 (USF1) to the human SHP promoter. In addition, in vivo administration of SHP-inducing drugs effectively protects against LPS-induced lethal shock and folic acid-induced acute tubular necrosis. MD2, lymphocyte antigen 96; TRAM, Trif-related adaptor molecule; TRIF, Toll/IL-1 receptor domain-containing adaptor inducing β; RON, recepteur d'origine nantais; NBD, nucleotide-binding domain; CARD, caspase activation and recruitment domains; PYD, pyrin domain; ASC, adaptor protein apoptosis-associated speck-like protein containing a caspase recruitment domain; IRAK1, interleukin-1 receptor-associated kinase 1; IKK, IκB kinase.

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