The role of caloric load and mitochondrial homeostasis in the regulation of the NLRP3 inflammasome

Abstract

Sterile inflammation is a cornerstone of immune activation in obesity and type 2 Diabetes Mellitus. The molecular underpinnings of this inflammation include nutrient excess-mediated activation of the innate immune NLRP3 inflammasome. At the same time, disruption of mitochondrial integrity is emerging as an integral control node in NLRP3 inflammasome activation and is also associated with caloric overload conditions including obesity and diabetes. Conversely, caloric restriction and fasting mimetic interventions alleviate these caloric excess-linked diseases and reduce inflammation and the NLRP3 inflammasome. The objective of this review is to integrate the findings linking mitochondrial integrity to the activation of the NLRP3 inflammasome and to evaluate how caloric restriction or caloric restriction mimetic compounds may play a role in attenuating the NLRP3 inflammasome and sterile inflammation.

Metabolic Disorder in Chronic Obstructive Pulmonary Disease (COPD) Patients: Towards a Personalized Approach Using Marine Drug Derivatives

“…NLRP3 inflammasome is implicated in the progression of different non-communicable diseases. Surplus levels in nutrients associated with caloric overload as well as low-level of circulatory endotoxemia (LPS), as in the case of obesity, cause NLRP3 activation playing an important role in the perpetuation of insulin resistance and inflammation [109]. High expression of the NLRP3 genes is observed in the abdominal subcutaneous adipose tissue in obese adolescents [110] as well as in COPD patients [111].…”

Angeborene Immunität und Adipositas – Die Rolle der Nod-like-Rezeptoren (NLR)

“…Oxidativer Stress und damit die vermehrte Produktion reaktiver Sauerstoffspezies (engl. reactive oxygen species, ROS) in den Mitochondrien des Fettgewebes bei starkem Kalorienüberschuss [84,85] könnten dabei sowohl zum Priming [83] als auch zur Aktivierung des NLRP3-Inflammasoms [86,87] beitragen. Eine weitere Theorie führt Stress im Endoplasmatischen Retikulum (ER) als potenziellen Aktivator des NLRP3-Inflammasoms im Pankreas an.…”

Mitochondrial fidelity and metabolic agility control immune cell fate and function

“…The inflammasome is a multiprotein complex that assembles and self-oligomerizes to promote cleavage and activation of canonical cytokines, namely IL-1β and IL-18, to amplify immune responses (63,64). The nucleotide oligomerization domain-like (NOD-like) receptor family pyrin domain 3 (NLRP3) inflammasome is activated by sterile inflammation associated with crystal-linked diseases like gout, and by metabolic diseases including obesity, diabetes, hyperlipidemia, and cardiovascular disease (65), and its activation further exacerbates these diseases (66)(67)(68)(69). For example, in obesity, the inflammasome is initiated through adipose tissue hypertrophy with macrophage infiltration and cytokine secretion; elevated circulating saturated fatty acids, glucose, and lipids; and/or obesity-linked endotoxemia mediated by upregulation of NLRP3 and its canonical cytokines (pro-IL-1β and pro-IL-18) via NF-κB (70)(71)(72)(73).…”

“…Following priming, subsequent activation is instigated by assembly and oligomerization of canonical inflammasome constituents (65). NLRP3 complex oligomerization initiates caspase-1 activation and cleavage of pro-IL-1β and pro-IL-18 into bioactive cytokines that function to amplify inflammation (63,64).…”

“…Taken together, there is evidence of considerable overlap between mitochondrial cargo-triggered immune surveillance programs, and it is conceivable that they may function independently and/or may be coordinately activated (56,57). Additional studies are required to assess whether shared or distinct mechanisms of mtDNA extrusion and mitochondrial ROS signaling (65,116), as well as different mtDNA species, dictate engagement of these various intracellular immune surveillance sensors.…”