SCAPING Inflammation!

By Krystal Villalobos-Ayala

Endothelial cells (EC) respond to a plethora of external stimuli (i.e. infection,
inflammatory cytokines) and with constant activation of EC can lead to atherosclerosis and
recruitment of inflammatory immune cells. The relationship between inflammation and
cholesterol homeostasis has only been studied in atherosclerosis, however, the mechanism of
action has not been elucidated.
Fowler et al, show the close relationship between inflammatory signaling (TNF-α→NF-
kB) and cholesterol homeostasis (SCAP-SREBP complex). The authors show that inflammatory
pathways and the cholesterol biosynthesis pathway is upregulated in cells upon TNF-α
introduction, which is all dependent on Rela (activator of NF-kB). TNF-α increases SREBP2
cleavage, which activates it, and cholesterol biosynthesis proteins are produced. The authors
then investigated step by step of how the cholesterol biosynthesis pathway is upregulated using
biochemical and genetic assays. The authors found that the TNF-α activation of SREBP2 in
cells is dependent both on NF-kB activation with Rela and its DNA-binding ability to increase the
production STARD10. STARD10 regulates trafficking of cholesterol and may be implicated in
reorganization of plasma membrane lipids which may affect cholesterol flux. The alteration of
accessible cholesterol is sensed by the SCAP/SREBP2 complex. The authors also show that
shuttling of the SCAP/SREBP2 complex from one cell compartment to the next (endoplasmic
reticulum to the Golgi) in TNF-α treated cells is essential in cleaving/activating SREBP2. An
activated SREBP2 is now able to produce the proteins involved in cholesterol biosynthesis.
Fowler et al, mechanistically characterized how inflammation affects cholesterol
homeostasis. Moreover, more studies need to be done in a model of chronic inflammation to
explore how SREBP2 activation affects endothelium vascular permeability, receptor signaling
and sensitivity to infections.

A selected paper highlight for Fowler et al. 2022 from a pool of research highlights,
Cancer Immunotherapy class of 2023

written by Krystal Villalobos-Ayala, University of South Florida PhD Program