INSIGHTS | PERSPECTIVES
old mice, indicating that the LXR signaling
pathway is diminished when mice age.
RXR is a key regulator of lipid metabolism
and immune function in macrophages (9).
Similar to LXR, RXR signaling pathways are
significantly down-regulated in aged myelin-phagocytic human monocytes (precursor
cells that differentiate into macrophages) (6).
Furthermore, the macrophage-specific ablation of RXR signaling results in decreased
myelin clearance and delayed remyelination,
suggesting a possible role for RXR-regulated
cholesterol efflux in remyelination (6).
Cantuti-Castelvetri et al. show that the
formation of cholesterol crystals in the lysosomes of phagocytes is associated with the
limited recovery of demyelinated lesions
displayed by mice deficient in LXR signaling. Cholesterol crystals are thought to de-stabilize the lysosome, resulting in leakage
of cathepsin B and induction of inflammation through activation of NLRP3 (NACHT,
LRR, and PYD domains containing protein
3) inflammasome activity. They found that
NLRP3 inflammasome activity recruits and
activates caspase-1, which promotes the
release of the inflammatory cytokine inter-
leukin-1b (IL-1b) in the demyelinated lesion
(see the figure). Nevertheless, it remains
unclear how inflammasome activation di-minishes remyelination in aged animals.
It is possible that unresolved inflammation
(caused by defective cholesterol efflux) delays the conversion of macrophages from
proinflammatory to anti-inflammatory, a
switch that drives OPC differentiation (10).
Another possibility is that the regenerative environment is compromised because
of the inflammatory (pyroptotic) death of
macrophages mediated by caspase-1.
The study of Cantuti-Castelvetri et al. also
highlights an interesting parallel between the
molecular defects of macrophages in older
demyelinated lesions and the development of
atherosclerosis, in which plaques comprised
of molecules, including cholesterol, build up
in arteries. The prevailing model of athero-
sclerosis pathogenesis centers on the inability
of macrophages to effectively mobilize cho-
lesterol through LXR-RXR–mediated efflux
(8). Thus, LXR and RXR have become poten-
tial therapeutic targets in the effort to restore
cholesterol homeostasis in atherosclerosis.
Several LXR agonists, including GW3965,
have been developed to stimulate cholesterol
efflux from lipid-laden macrophages and in-
hibit the development of atherosclerosis (11).
Encouragingly, Cantuti-Castelvetri et al. show
that the administration of GW3965 to older
mice with demyelinated CNS lesions resulted
in enhanced clearance of myelin debris, re-
duced cholesterol-crystal formation in associ-
ated phagocytes, and significantly improved
remyelination. LXR agonists promote the
remyelination of rat cerebellar cultures that
have been experimentally demyelinated (12).
Similarly, the RXR agonist 9-cis-retinoic acid
enhances remyelination in aged mice, and
the RXR agonist bexarotene confers a gene-
expression profile associated with phagocytes
from younger individuals and enhanced
myelin-debris clearance by phagocytes from
MS patients (6, 13). Bexarotene is being tested
in an MS clinical trial (European Union Clini-
cal Trials Register no. 2014-003145-99).
The discovery of the link between cholesterol crystal–laden macrophages and inflammasome activation in demyelinated lesions
provides a deeper understanding of remyelination failure in MS patients, particularly
as the disease progresses. Currently, there
are numerous approved drugs for MS, all of
which modulate immune responses to some
extent. Although beneficial, these drugs fail
to curtail the progressive neurodegeneration
that occurs in this chronic neurological disorder (14). New therapeutic approaches designed to provide neuroprotection (15) and
enhanced remyelination, such as by targeting LXR-RXR (2), would likely complement
the current anti-inflammatory drugs to provide increased clinical benefit. j
REFERENCES AND NOTES
1. S.L.Hauser etal., Ann.Neurol.74,317(2013).
2. R.J.M.Franklin,C.ffrench-Constant, Nat. Rev. Neurosci.18,
3. L. Cantuti-Castelvetri etal. ,Science 359, 684 (2018).
4. M.Simons, K.-A.Nave, Cold SpringHarb.Perspect.Biol.8,
5. D.E.Bergles,W.D.Richardson, Cold SpringHarb.Perspect.
Biol. 8, a020453 (2015).
6. M.S.Natrajan etal.,Brain 138,3581(2015).
7. J.M.Ruckh et al., Cell Stem Cell 10,96(2012).
8. K. J. Moore et al ., Nat. Rev. Immunol.13, 709 (2013).
9. T. Rőszer etal ., Trends Endocrinol.Metab .24, 460 (2013).
10. V.E.Miron etal., Nat.Neurosci.16,1211(2013).
11. C.Hong,P. Tontonoz, Nat.Rev.DrugDiscov.13,433(2014).
12. D. Meffre etal., Proc.Natl.Acad.Sci.U.S.A.112, 7587 (2015).
13. J.K.Huang etal., Nat.Neurosci.14,45(2011).
14. C. A. Dendrou, L. Fugger, Curr.Opin.Immunol .49, 37 (2017).
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ACKNO WLEDGMEN TS
B.P. is supported by grants from the National Institutes of
Health (NS034939, NS099334), the National Multiple Sclerosis
Society (RG-1501-02797), and the Dr. Miriam and Sheldon G.
Adelson Medical Research Foundation.
an interesting parallel
between the molecular
defects of macrophages in
older demyelinated lesions
and the development of
on the wing
Videos of more than 200
hummingbirds reveal the
evolutionary basis of
their maneuvering skills
By Peter C. Wainwright
Like other modes of locomotion, pow- ered flight is characterized by an ability to quickly change direction and speed. This ability—termed maneuverabil- ity—has far-reaching implications for animal success and survival (1, 2) but
is challenging to study because it includes a
wide range of distinct behaviors and is characterized by spontaneity. As a result, understanding of maneuverability is incomplete at
best (2–4). On page 653 of this issue, Dakin
et al. (5) probe the evolution of flight maneuverability in hummingbirds, which can hover
with precision and skillfully use a wide range
of acrobatic maneuvers (see the photos).
They show that a small number of underlying traits can explain much of the diversity of
maneuvering flight in hummingbirds.
Maneuverability involves rapid integration of sensory information by the central
nervous system, as well as the physical
ability of the animal to elude obstacles as
it moves through its environment, often at
breakneck speed. Both the complexity and
diversity of these maneuvers is difficult to
study. This is why Dakin et al. did not challenge hummingbirds with a series of specific locomotor tasks. Rather, by extending
a recent trend in the study of animal flight
(6, 7), they used video recorders to document the diversity and performance of specific maneuvers used by birds housed in an
enclosure as they flew about, perched, and
fed from a source of artificial nectar. The research team included more than 200 birds
from 25 species in the survey, which yielded
flight behavior profiles for each species
under study. These profiles proved to be
largely diagnostic of species: Different spe-
Department of Evolution and Ecology, University of California,
Davis, Davis, CA 95616, USA. Email: email@example.com