The interplay between innate immunity and metabolism in the retinal pigment epithelium

  • Louis M Scott

Student thesis: Doctoral ThesisDoctor of Philosophy (PhD)

Abstract

All cells must be able to tailor their energetic resources to different conditions both in quiescent and stress contexts. The retinal pigment epithelium (RPE) provides a highly dynamic model system to study basic cellular metabolism due to its extremely active mitochondrial capacity, which maintains retinal homeostasis and compensates the noxious effects of oxidative damage to the tissue. RPE stress, inflammasome activation and metabolic alterations with mitochondrial dysfunction have been implicated in retinal diseases. However, the causal link between stress, metabolic alterations and retinal degeneration remains unclear.

There are important symbiotic interactions between immune responses and core intracellular metabolic pathways. Specific alterations in metabolism couple to immune effector functions, most notably resulting in a programmed production of distinct sets of cytokines. To this end, immune cells with different functions use several different metabolic pathways to generate adequate levels of energy stores to (A) support survival and (B) to facilitate the highly expensive production of numerous biosynthetic intermediates. Conversely, evidence suggests that intracellular metabolites themselves may modulate immune function. This thesis highlights the interplay between immune responses and cellular metabolism in the RPE (a non-haemopoietic innate immune cell responsible for immune privilege in the retina). Key components of the RPE innate immune response are responsible for the remodelling of metabolic pathways through innate immune receptor signalling and nuclear control over protein expression.

A decline in mitochondrial capacity with age may limit the ability of a cell to divert energy sources and maintain optimum retinal health. The data presented suggest that the activity of the energy sensor AMP-activated kinase (AMPK) is fundamental to maintaining innate immune and metabolic function within the RPE. AMPK acts as a “built-in brake system” to limit aerobic glycolysis and anabolic metabolism, whilst simultaneously increasing mitochondrial function. During innate immune activation, altering the activation state of AMPK allows different Toll-like receptor (TLR) agonists to elicit alternate RPE metabolic phenotypes.

Data presented have identified the “alarmin” interleukin-33 (IL-33) as a key regulatory node of RPE metabolism. Activation of the IL-33/ST2 axis is supported metabolically by mitochondrial respiration. Through bolstering mitochondrial activity, exogenous IL-33 administration protects RPE cells against oxidative damage, accompanied by the increased expression of PGC-1α and other metabolic regulators. In addition to its extracellular function, endogenous IL-33 expression status influences metabolic regulation in RPE cells. IL-33 loss constrains oxidative glucose catabolism, as IL-33 was found to regulate pyruvate import into the mitochondria through the mitochondrial pyruvate carrier (MPC) complex. In contrast, cells overexpressing IL-33 display increased expression of MPC complex components and activity of pyruvate dehydrogenase to facilitate increased pyruvate flux into the TCA cycle.

IL-33 retains its nuclear localisation in vitro under multiple conditions of inflammatory stress and interacts with a dynamic network of proteins. Moreover, it is observed that nuclear IL-33 regulates protein expression of human and murine RPE cells and contributes to the regulation of metabolic enzyme splicing. These support the current view of IL-33 as a dual function protein with functional roles in the nucleus. As IL-33 and its nuclear interactions are enhanced or dampened in response to inflammatory cues, this indicates that intrinsic IL-33 acts as a key node to maintain cellular metabolic profiles and likely facilitate innate immune responses separate from its extracellular functions.
Date of Award28 Nov 2019
Original languageEnglish
Awarding Institution
  • The University of Bristol
SupervisorAndrew David Dick (Supervisor) & Sofia Theodoropoulou (Supervisor)

Cite this

The interplay between innate immunity and metabolism in the retinal pigment epithelium
Scott, L. M. (Author). 28 Nov 2019

Student thesis: Doctoral ThesisDoctor of Philosophy (PhD)