![n engl j med 371;20 nejm.org november 13, 2014 1933
clinical implications of basic research
The new engl and jour nal of medicine
Elizabeth G. Phimister, Ph.D., Editor
Cholesterol Metabolism and Immunity
Anna Simon, M.D., Ph.D.
Research from both the bench and the clinic has
provided increasing evidence for cross-talk be-
tween cholesterol metabolism and the immune
system, providing a greater understanding of host
response to infection and of the inflammatory
components of cardiovascular disease, such as
atherosclerosis. A recent example is research by
Reboldi et al.1 showing that 25-hydroxycholesterol
tightly regulates interleukin-1β, a potent cytokine.
The metabolite 25-hydroxycholesterol is an oxy
sterol and is derived from cholesterol (Fig. 1A).
Although it influences cholesterol homeostasis
by means of the suppression of sterol regulatory
element–binding proteins (SREBPs),2 its main
effect appears to be on immune regulation. The
most potent enzyme that transforms cholesterol
into 25-hydroxycholesterol is cholesterol 25-hy-
droxylase (CH25H), which is prominently pro-
duced in monocytes, macrophages, and den-
dritic cells — the major cell types of the innate
immune system synthesizing interleukin-1β.
(CH25H is not expressed in the liver, the organ
most active in synthesizing fatty acids and cho-
lesterol.) Mice lacking Ch25h have normal choles-
terol homeostasis (and also synthesize small
amounts of 25-hydroxycholesterol) but have
marked changes in their inflammatory response.1
The expression of CH25H is very strongly in-
duced by lipopolysaccharide, by type I interfer-
ons — important antiviral cytokines, one of
which (interferon-β) is used to treat the inflam-
matory disease multiple sclerosis — and by viral
infection, leading to increased concentrations of
25-hydroxycholesterol.2 Reboldi et al. found that
25-hydroxycholesterol mediates the inhibition of
interleukin-1β induced by type I interferon.1
More specifically, 25-hydroxycholesterol inhibits
pro–interleukin-1β gene transcription as well
as the inflammasome-mediated activation of
interleukin-1β (Fig. 1B) by inhibiting the activa-
tion of SREBP. They found that the macrophages
of Ch25h-knockout mice produce more inter
leukin-1β when exposed to lipopolysaccharide
and that this can be corrected by adding 25-hy-
droxycholesterol to the culture medium. The
Ch25h-knockout mice were more susceptible than
wild-type mice to lipopolysaccharide-induced
lethality because of increased cytokine production.
A rare hereditary disease linking cholesterol
metabolism and inflammation is mevalonate
kinase deficiency. Mevalonate kinase is an early
enzyme in the cholesterol pathway (Fig. 1A), and
mutations in the mevalonate kinase gene cause
a substantial reduction in enzyme activity. Pa-
tients with mevalonate kinase deficiency have
lifelong recurring episodes of generalized in-
flammation with fever, mediated by cytokines
such as interleukin-1β.3 Many patients with me-
valonate kinase deficiency have increased serum
concentrations of IgA and IgD, and such in-
creased concentrations are also seen in mice de-
ficient in mevalonate kinase. The current hy-
pothesis is that defective protein isoprenylation
(resulting in the diminished activation of guan-
osine triphosphatases [GTPases]) represents the
link between a deficiency of mevalonate kinase
and inflammation (Fig. 1A). But a deficiency in
25-hydroxycholesterol is also a hypothetical link,
the more so because 25-hydroxycholesterol also
affects B cells. Ch25h-knockout mice also have
increased serum levels of IgA. In addition, it is
well known that viral infection (and vaccina-
tion) can provoke an inflammatory attack in per-
sons with mevalonate kinase deficiency.
Although a prompt inflammatory response is
important in combating pathogens, an overly
robust inflammatory response can damage the
host and cause complications. Containing in-
flammation as soon as the infection is under
control is therefore important. The inhibition
of interleukin-1β by 25-hydroxycholesterol may
represent a containment mechanism. Several
studies have shown other inhibitory roles of
25-hydroxycholesterol in cell models of viral in-](https://image.slidesharecdn.com/2014cholesterolmetabolismandimmunity-clinicalimplications-160418021108/85/2014-cholesterol-metabolism-and-immunity-clinical-implications-1-320.jpg)
2014 cholesterol metabolism and immunity clinical implications
- 1. n engl j med 371;20 nejm.org november 13, 2014 1933 clinical implications of basic research The new engl and jour nal of medicine Elizabeth G. Phimister, Ph.D., Editor Cholesterol Metabolism and Immunity Anna Simon, M.D., Ph.D. Research from both the bench and the clinic has provided increasing evidence for cross-talk be- tween cholesterol metabolism and the immune system, providing a greater understanding of host response to infection and of the inflammatory components of cardiovascular disease, such as atherosclerosis. A recent example is research by Reboldi et al.1 showing that 25-hydroxycholesterol tightly regulates interleukin-1β, a potent cytokine. The metabolite 25-hydroxycholesterol is an oxy sterol and is derived from cholesterol (Fig. 1A). Although it influences cholesterol homeostasis by means of the suppression of sterol regulatory element–binding proteins (SREBPs),2 its main effect appears to be on immune regulation. The most potent enzyme that transforms cholesterol into 25-hydroxycholesterol is cholesterol 25-hy- droxylase (CH25H), which is prominently pro- duced in monocytes, macrophages, and den- dritic cells — the major cell types of the innate immune system synthesizing interleukin-1β. (CH25H is not expressed in the liver, the organ most active in synthesizing fatty acids and cho- lesterol.) Mice lacking Ch25h have normal choles- terol homeostasis (and also synthesize small amounts of 25-hydroxycholesterol) but have marked changes in their inflammatory response.1 The expression of CH25H is very strongly in- duced by lipopolysaccharide, by type I interfer- ons — important antiviral cytokines, one of which (interferon-β) is used to treat the inflam- matory disease multiple sclerosis — and by viral infection, leading to increased concentrations of 25-hydroxycholesterol.2 Reboldi et al. found that 25-hydroxycholesterol mediates the inhibition of interleukin-1β induced by type I interferon.1 More specifically, 25-hydroxycholesterol inhibits pro–interleukin-1β gene transcription as well as the inflammasome-mediated activation of interleukin-1β (Fig. 1B) by inhibiting the activa- tion of SREBP. They found that the macrophages of Ch25h-knockout mice produce more inter leukin-1β when exposed to lipopolysaccharide and that this can be corrected by adding 25-hy- droxycholesterol to the culture medium. The Ch25h-knockout mice were more susceptible than wild-type mice to lipopolysaccharide-induced lethality because of increased cytokine production. A rare hereditary disease linking cholesterol metabolism and inflammation is mevalonate kinase deficiency. Mevalonate kinase is an early enzyme in the cholesterol pathway (Fig. 1A), and mutations in the mevalonate kinase gene cause a substantial reduction in enzyme activity. Pa- tients with mevalonate kinase deficiency have lifelong recurring episodes of generalized in- flammation with fever, mediated by cytokines such as interleukin-1β.3 Many patients with me- valonate kinase deficiency have increased serum concentrations of IgA and IgD, and such in- creased concentrations are also seen in mice de- ficient in mevalonate kinase. The current hy- pothesis is that defective protein isoprenylation (resulting in the diminished activation of guan- osine triphosphatases [GTPases]) represents the link between a deficiency of mevalonate kinase and inflammation (Fig. 1A). But a deficiency in 25-hydroxycholesterol is also a hypothetical link, the more so because 25-hydroxycholesterol also affects B cells. Ch25h-knockout mice also have increased serum levels of IgA. In addition, it is well known that viral infection (and vaccina- tion) can provoke an inflammatory attack in per- sons with mevalonate kinase deficiency. Although a prompt inflammatory response is important in combating pathogens, an overly robust inflammatory response can damage the host and cause complications. Containing in- flammation as soon as the infection is under control is therefore important. The inhibition of interleukin-1β by 25-hydroxycholesterol may represent a containment mechanism. Several studies have shown other inhibitory roles of 25-hydroxycholesterol in cell models of viral in-
- 2. The new engl and jour nal of medicine n engl j med 371;20 nejm.org november 13, 20141934 fection, such as the inhibition of viral entry into the cell, and in the inhibition of viral replica- tion.4 On the other hand, Gold et al.,5 using a systems biology approach, found that 25-hydroxy- cholesterol amplifies inflammation. They found that Ch25h-knockout mice are more likely than wild-type mice to survive influenza, owing to less inflammatory damage. Additional studies are required to resolve the conundrum. Statins, which are 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors (Fig. 1A), have been suggested to confer a sur- vival benefit in influenza, although hard evi- dence is still lacking. Diverse antiinflammatory effects, as well as some proinflammatory ef- fects,2 have been attributed to statins. So far, however, the effects of either statins or hyper- cholesterolemia on macrophage production of 25-hydroxycholesterol are unclear. Although questions remain unanswered, the study by Reboldi et al. offers insight into the role of 25-hydroxycholesterol in immunity and, more specifically, into the host response against viral infection. With the current multiple viral threats to populations around the world, new insights into the host response to viral infection — which may provide fodder for new clinical approaches to treatment — are more than welcome. Disclosure forms provided by the author are available with the full text of this article at NEJM.org. From the Department of Internal Medicine, Radboud University Medical Center, Nijmegen, the Netherlands. 1. Reboldi A, Dang EV, McDonald JG, Liang G, Russell DW, Cyster JG. 25-Hydroxycholesterol suppresses interleukin-1-driven inflammation downstream of type I interferon. Science 2014; 345:679-84. 2. Spann NJ, Glass CK. Sterols and oxysterols in immune cell function. Nat Immunol 2013;14:893-900. 3. Masters SL, Simon A, Aksentijevich I, Kastner DL. Horror autoinflammaticus: the molecular pathophysiology of autoin- flammatory disease. Annu Rev Immunol 2009;27:621-68. Macrophage Nucleus A 25-Hydroxycholesterol Synthesis Acetate HMG-CoA Type I interferon Toll-like receptor 4 Type I interferon receptor Lipopolysaccharide Mevalonate Protein isoprenylation Cholesterol Cholesterol 25-hydroxycholesterol 25-hydroxycholesterol Inflammasome activation Transcription Transcription B Interleukin-1β Inhibition Cholesterol Transcription Transcription Transcription TranscriptionTranscriptionTranscriptionTranscriptionTranscription HMG-CoA reductase Mevalonate kinase Statins Cholesterol 25-hydroxylase Il1b Mevalonate kinase deficiency Ch25h Interleukin-1βPro–interleukin-1β Ch25h AUTHOR: FIGURE: ARTIST: OLF:Issue date: AUTHOR, PLEASE NOTE: Figure has been redrawn and type has been reset. Please check carefully. Simon - cibr1412016 1 of 1 AB 11-13-14 Figure 1. Derivation of 25-Hydroxycholesterol and the Inhibition of Interleukin-1β by 25-Hydroxycholesterol. Panel A shows a simplified representation of the cholesterol pathway, with three activating enzymes indicated in green. Statins are inhib- itors of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase. The genetic defect in mevalonate kinase deficiency is located in mevalonate kinase. Panel B shows that the production of 25-hydroxycholesterol is induced by type I interferons, released during viral in- fection, and also by lipopolysaccharide. The metabolite 25-hydroxycholesterol reduces the production of interleukin-1β by the inhibition of pro–interleukin-1β transcription and by the inhibition of activation of pro–interleukin-1β by inflammasomes. Ch25h denotes choles- terol 25-hydroxylase, and Il1b the gene encoding interleukin-1β.
- 3. n engl j med 371;20 nejm.org november 13, 2014 1935 clinical implications of basic research 4. Liu SY, Aliyari R, Chikere K, et al. Interferon-inducible choles- terol-25-hydroxylase broadly inhibits viral entry by production of 25-hydroxycholesterol. Immunity 2013;38:92-105. 5. Gold ES, Diercks AH, Podolsky I, et al. 25-Hydroxycholes- terol acts as an amplifier of inflammatory signaling. Proc Natl Acad Sci U S A 2014;111:10666-71. DOI: 10.1056/NEJMcibr1412016 Copyright © 2014 Massachusetts Medical Society.