By Peter Stilz
Bats often navigate rapidly through complex environments by using echolocation, a sensory modality that is profoundly different from hu- man vision (1). Building a sufficient hree-dimensional perception of
their environment on a lower-dimensional
sensory input than human vision, they perform a complex task. They are thus forced
to apply a high degree of processing and
interpretation to the sensory input, making them prone to sensory deceptions.
On page 1045 of this issue, Greif et al. (2)
report that vertical mirrorlike reflecting
surfaces, which bats perceive as open flyways, can act as sensory traps.
Bat echolocation differs from human vi-
sion with respect to which environmental
features are directly accessible, and which
must be extracted through advanced
mechanisms. Binocular vision provides hu-
mans with a continuous flow of two sepa-
C/EBP-homologous protein (CHOP) (2).
This pathway is identical to the mecha-
nism that triggers canonical autophagy
in Paneth cells upon deletion of the gene
encoding the UPR transcription factor, X
box–binding protein–1 (XBP1) (1). Although
ER stress causes a mild form of enteritis
in Xbp1DIEC mice (7), loss of PERK-induced
autophagy in Atg16l1;Xbp1DIEC mice re-
sults in a transmural, discontinuous ileitis
reminiscent of human Crohn’s disease (1).
Notably, in Xbp1DIEC mice, CHOP signal-
ing induces the expression of the NKG2D
ligand UL16-binding protein 1 (ULBP1),
which causes an increase in NKG2D-
expressing ILC1s and natural killer im-
mune cells in the intraepithelial compart-
ment (8). This is interesting because Bel
et al. found that S. Typhimurium–induced
IL-22 secretion from ILC3s is required for
triggering lysozyme release via secretory
autophagy in Paneth cells with ER stress
(2). This raises the possibility that ER
stress in IECs serves as a means to sense
the presence of pathogens, creating a bi-
directional system of communication that
involves different subsets of immune cells
that are ultimately involved in pathogen
control. This may be a primitive function
of ER stress in the IEC as shown by the
critical role played by IRE1a, the most evo-
lutionarily conserved of the three branches
of the UPR, in allowing the roundworm,
Caenorhabditis elegans, to resist infection
by Pseudomonas aeruginosa (9).
IRE1a is an ER transmembrane receptor that forms homodimers upon ER stress,
increasing to large clusters when ER stress
persists. This is associated with a change
from triggering a resolving UPR to one associated with inflammation (10). During
persistent ER stress, a selective ATG16L1-
dependent autophagy process is required
to remove IRE1a clusters and to terminate
its signaling (11). Indeed, in patients with
ATG16L1 T300A and in Atg16l1DIEC mice, IRE1a
accumulates in Paneth cells (11). In a related pathway, NOD2 signaling triggers IkB
kinase a (IKKa) activation, which directly
phosphorylates and stabilizes ATG16L1 (12).
In the absence of IKKa, removal of IRE1a
clusters is disrupted (12). With increasing
age, Atg16l1DIEC mice develop Crohn’s disease–like ileitis (11) similar to the ileitis in
young Atg16l1;Xbp1DIEC mice (1), and both
types of ileitis are driven by accumulation
and hyperactivation of IRE1a (1, 11).
Whether NOD2 and immunity-related
GTPase family M (IRGM), another au-
tophagy pathway genetic risk element for
Crohn’s disease (13), contribute to secretory
autophagy and/or the ileitis-inducing path-
way described above will be interesting to
explore. Notably, in myeloid cells infected
with Brucella abortus, NOD2 is engaged
downstream of IRE1a activation and medi-
ates ER stress–induced inflammation (14).
NOD2 further relays signals from the com-
mensal microbiota to leucine-rich repeat
kinase 2 (LRRK2, encoded by another gene
that is associated with Crohn’s disease) to
sort lysozyme into the secretory pathway,
preventing its lysosomal degradation (4).
Consequently, impaired function of NOD2,
LRRK2, and IRGM all manifest with phe-
notypic abnormalities in the Paneth cell
secretory compartment (4, 15). It is this
remarkable convergence of Paneth cell
phenotypes resulting from the impairment
of important genes associated with risk of
developing Crohn’s disease that renders the
underlying mechanisms of relevance for un-
derstanding Crohn’s disease pathogenesis.
The majority of the genetic defects associated with Paneth cell dysfunction are
not associated with spontaneous disease
in genetically deficient mice. This highlights the critical role of the environment
in triggering disease in genetically susceptible individuals. Only these yet-to-be defined environmental factors can provide
the critical insights needed to explain the
global increase in incidence and prevalence
of Crohn’s disease observed over recent decades. It is interesting in this regard that
exposures to numerous types of entero-pathogens represent one of the greatest
environmental risk factors for the development of Crohn’s disease. The study of Bel
et al. may therefore provide an interesting
link between these and other epidemiologic
observations and the genetic landscape of
Crohn’s disease. j
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The authors’ laboratories are supported by a Wellcome Trust
Senior Investigator Award 106260/Z/14/Z (A.K.), the European
Research Council HORIZON2020/ERC grant no. 648889 (A.K.),
and NIH grant DK018839 (R.S.B.).
Bats fail to perceive vertical
such as large windows,
and collide with them
Department of Animal Physiology, Institute
for Neurobiology, University of Tübingen, Germany.
A greater mouse-eared
bat navigates through