Mitochondrial Control of Innate Immunity and Inflammation

Mitochondria are key organelles involved in energy production, functioning as the metabolic hubs of cells. Recent findings emphasize the emerging role of the mitochondrion as a key intracellular signaling platform regulating innate immune and inflammatory responses. Several mitochondrial proteins and mitochondrial reactive oxygen species have emerged as central players orchestrating the innate immune responses to pathogens and damaging ligands. This review explores our current understanding of the roles played by mitochondria in regulation of innate immunity and inflammatory responses. Recent advances in our understanding of the relationship between autophagy, mitochondria, and inflammasome activation are also briefly discussed. A comprehensive understanding of mitochondrial role in toll-like receptor-mediated innate immune responses and NLRP3 inflammasome complex activation, will facilitate development of novel therapeutics to treat various infectious, inflammatory, and autoimmune disorders.

Small Heterodimer Partner and Innate Immune Regulation

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.

Toll-like Receptors and NOD-like Receptors in Innate Immune Defense during Pathogenic Infection

In response to invading pathogens, the body immune system develops an immediate defense mechanism, i.e., innate immune response, which is detected in almost all living organisms including mammals, plants, insects, etc. Recent studies have identified numerous innate immune receptors that are able to recognize pathogen-associated molecular patterns and transduce the essential intracellular signaling cascades to mount early and successful host defenses against infectious challenge. Among innate immune receptors, we will focus on two important receptors, toll-like receptors (TLRs) and nucleotide binding oligomerization domain (Nod)-like receptors, and their major intracellular signaling pathways that culminate to activate innate immune effectors and inflammatory mediators during pathogen infection. In this review, we address the recent advances of understanding intracellular signaling mechanisms by which TLRs and NLRs activate host immune defense and inflammation. The role and regulatory mechanisms by which a subet of NLRs-associated inflammasome activation induce interleukin-1beta secretion and their relevance with host defense will be also discussed. Both TLR- and NLR-mediated intracellular signaling networks serve crucial roles in mounting resistance to bacterial and viral infection through synthesis of immune mediators and antimicrobial chemicals during infection.