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The Journal of Clinical Investigation COMMENTARY
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The role of 15 lipoxygenase 1 in asthma comes into focus
Joshua A. Boyce
Division of Allergy and Clinical Immunology, Department of Medicine, Brigham and Women’s Hospital, Boston, Massachusetts, USA.
Altered epithelial cell
differentiation in chronic
respiratory tract inflammation
Asthma and chronic rhinosinusitis with
nasal polyposis CRSwNP are prevalent
immune-mediated diseases of the respira-
tory tract that frequently coexist and cause
substantial morbidity . CRSwNP and
asthma are most often associated with
eosinophilic respiratory tissue iniltration,
mast cell hyperplasia, goblet cell metapla-
sia, and disrupted epithelial integrity ,
processes that are linked to the actions of
type T cytokines type inflammation;
ref. . Speciically, cytokines IL and IL
alter epithelial cell differentiation trajecto-
ries and function while strongly inducing
the expression of a cassette of characteristic
transcripts e.g., MUCAC, CLCA, CCL,
POSTN, and INOS in local stromal cells
by signaling though the α subunit of the
IL receptor ILRα , . The strength
of expression of these ILRα–driven tran-
scripts in bronchial and nasal mucosal epi-
thelial cells correlates with indices of dis-
ease severity , . Moreover, the eficacy of
a humanized monoclonal antibody against
ILRα dupilumab in the treatment of
severe T-high asthma and CRSwNP vali-
dates the biological importance of ILRα–
inducible products in disease patho-
physiology , , although the relative
contributions of each remain less clear.
Pro- and antiinflammatory
functions of 15LO1 products
ALOX, encoding lipoxygenase
LO, is one of the strongly and con-
sistently expressed ILRα–inducible
transcripts by mucosal epithelial cells
in T-high asthma and CRSwNP , ,
. Its expression is especially strong in
aspirin-exacerbated respiratory disease
AERD, a disease phenotype that is over-
represented in the most severely affected
patients with asthma and CRSwNP .
ALOX is also expressed inducibly by
macrophages and constitutively by eosin-
ophils . LO catalyzes the oxidation
of arachidonic acid AA and other poly-
unsaturated fatty acids PUFAs, forming
peroxy derivatives that are precursors of
diverse mediators. In contrast to other
lipoxygenase enzymes e.g., LO, LO,
LO introduces molecular oxygen spe-
cies into both free PUFAs and into PUFAs
that are esteriied in phosphatidyletha-
nolamine PE in cell membranes .
LO converts free AA to an unstable
hydroperoxide, OOH eicosatetraeno-
ic acid HpETE, which is rapidly reduced
to S-HETE. These intermediates are
converted in turn to diverse metabolites,
including -oxo-S-hydroxyeicosa-
tetraenoic acid -oxo-S-HETE, a
chemoattractant for human eosinophils
, eoxin C, a conjugate of HETE
to reduced glutathione GSH that is
generated by eosinophils , and other
less-well-characterized products. LO
also converts the granulocyte-derived
LO product leukotriene A to lipoxin A,
a mediator that resolves inflammation
. LO products abound in biologi-
cal fluids e.g., nasal lavage, bronchoal-
veolar lavage BAL from patients with
asthma and CRSwNP; ref. , reflecting
LO activity in vivo, and correlating
with disease severity. Understanding the
balance of pro- and antiinflammatory
functions of LO products is essential
to therapeutic targeting of this enzyme.
While soluble products of LO
activity reflect peroxidation of free
PUFAs, oxidative products of esteriied
PUFAs remain cell associated and are
therefore more challenging to study. Both
LO and its homologue, LO which
is constitutively expressed in several
organs, interact with cell membrane–
associated PE-binding protein PEBP, a
scaffolding protein that regulates mito-
gen-activated protein kinase MAPK cas-
cades . The interaction between PEBP
and LO permits IL to induce the
activation of extracellular signal–regu-
lated kinase ERK . Additionally, the
association with PEBP switches the sub-
strate preference of LO from free to
esteriied AA, resulting in the formation
of HpETE esteriied onto PE HpETE-
PE. Importantly, LO-derived HpETE-
PE is a potent trigger of ferroptosis ,
a form of iron-dependent programmed
cell death involving lipid peroxidation
Related Article: https://doi.org/10.1172/JCI151685
Conflict of interest: JAB is a member of the Scientific Advisory Boards of Sanofi/Aventis, Third Harmonic Bio, and Siolta
Therapeutics.
Copyright: © 2022, Boyce. This is an open access article published under the terms of the Creative Commons Attribution 4.0
International License.
Reference information: J Clin Invest. 2022;132(1):e155884. https://doi.org/10.1172/JCI155884.
IL-4– and IL-13–driven epithelial cell expression of 15 lipoxygenase 1 (15LO1)
is a consistent feature of eosinophil-dominated asthma known as type
2–high (T2-high) asthma. The abundant soluble products of arachidonic
acid (AA) metabolized by 15LO1 reflect a high level of enzymatic activity in
asthma and chronic rhinosinusitis. However, the precise role of 15LO1 and its
products in disease pathogenesis remains enigmatic. In this issue of the JCI,
Nagasaki and colleagues demonstrate a role for 15LO1 in controlling redox
balance and epithelial homeostasis in T2-high asthma by metabolizing AA
that is esterified to membrane phospholipids. The findings may pave the
way toward the development of 15LO1 inhibitors as asthma treatments.
The Journal of Clinical Investigation
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2J Clin Invest. 2022;132(1):e155884 https://doi.org/10.1172/JCI155884
upregulated LO protein expression.
Unexpectedly, IL also upregulated the
expression of both GPX and SLCA, a
glutamine transporter necessary to main-
tain intracellular GSH, suggesting a coor-
dinated cellular response to preserve redox
homeostasis. Stimulation of the cultured
cells with IL decreased both intra-
cellular and extracellular levels of GSH,
increased extracellular GSSH levels, and
decreased GSH/GSSH ratios in both com-
partments. Based on studies using small
interfering RNA knockdown and pharma-
cologic inhibition of LO in IL–stimu-
lated epithelial cells, the changes involved
LO. Intracellular GSH levels and GSH/
GSSH ratios in freshly obtained bronchial
epithelial cells correlated inversely with
LO expression levels but positively
with the SLCA/LO expression ratio
. Treatment of the IL–stimulated
epithelial cells with erastin, an inhibitor of
SLCA that depletes intracellular levels
of GSH, induced cell death while modest-
gators found higher glutathione disulide
GSSH reflecting the consumption of
GSH and lower GSH/GSSH ratios in BAL
fluids from subjects with severe asthma
than those with mild/moderate disease and
healthy controls. Intracellular GSH levels
and GSH/GSSH ratios were lowest in epi-
thelial cells from severe asthmatic subjects,
consistent with increased utilization of GSH
to maintain homeostasis. Both BAL fluid
and intracellular GSH/GSSH levels correlat-
ed inversely with the levels of exhaled nitric
oxide, a surrogate marker of T-driven INOS
expression, and correlated positively with
measures of lung function. These observa-
tions are consistent with altered redox bal-
ance in severe asthma that correlates with
both physiologic impairment and with sur-
rogate measures of T inflammation.
To understand the potential role of
ILRα–driven LO activity in altering
epithelial redox balance, the authors treat-
ed cultured bronchial epithelial cells with
IL ex vivo. As expected, IL strongly
. Glutathione peroxidase GPX
reduces PE-associated lipid peroxides
and prevents ferroptosis by convert-
ing HpETEPE to HETEPE, con-
suming GSH in the process. Diminished
expression of GPX or insuficient GSH
levels alter redox balance, favoring fer-
roptosis in the context of LOPEBP
interactions , a mechanism that may
potentially disrupt epithelial function and
barrier integrity Figure .
Controlling redox balance
in the airway
In this issue of the JCI, Nagasaki and
colleagues provide direct evidence that
LO-derived HpETEPE plays a role
in controlling redox balance in the airway
of patients with asthma, with potential
pathophysiologic consequences . Using
measures of redox balance in BAL fluids
and freshly harvested bronchial epithelial
cells from subjects with asthma who were
enrolled in two cohort studies, the investi-
Figure 1. Model for dual role of 15LO1 in asthma
related to type 2 inflammation. IL-4 and IL-13
induce IL-4Rα–dependent signaling to drive
ALOX15 (15LO1) expression in human airway
epithelial cells (HAECs). 15LO1 can add molecular
oxygen to free AA, forming HpETE that is rapidly
reduced to 15(S)-HETE, which in turn can be
converted into 5-oxo-15(S)-HETE, eoxin C4, and
other detectable mediators found in biological
fluids. 15LO1 also associates with PEBP in the
cell membrane, activating ERK (leading to
potentiated expression of additional type 2
inflammatory proteins) and switching the 15LO1
substrate preference to PE-esterified AA. The
resultant HpETE-PE triggers ferroptosis unless
it is reduced by GPX. This reduction requires
GSH, which is maintained by the glutamic acid
transporter protein SLC7A11. IL-13 increases both
GPX and SLC7A11 expression, suggesting that
a coordinated system maintains cellular redox
balance. Perturbations in this system, such as
diminished GSH availability, may favor ferro-
ptosis over cytoprotection, leading to epithelial
damage. Red color indicates proteins that are
upregulated in epithelial cells by IL-4 and IL-13.
The Journal of Clinical Investigation COMMENTARY
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J Clin Invest. 2022;132(1):e155884 https://doi.org/10.1172/JCI155884
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The study by Nagasaki et al.
directly implicates altered redox balance
in severe asthma, and links this altered bal-
ance to the induced expression and func-
tion of LO. Although the authors do not
directly demonstrate LO-mediated fer-
roptosis in vivo, it is tempting to speculate
that the altered barrier integrity observed
in both asthma and CRSwNP may at least
partly reflect this process. While no cur-
rently available drugs block LO activity
in humans, a loss-of-function mutation of
ALOX confers strong protection against
the development of CRSwNP in cohorts
from Sweden and the United Kingdom ,
strongly suggesting a key role for LO
and its products in ILRα–driven epithelial
functional changes, and potential for ther-
apeutic targeting of LO with inhibitors.
It is tempting to speculate that the success
of dupilumab as a treatment for asthma and
CRSwNP could at least partly reflect a res-
toration of epithelial function by preventing
ferroptosis and other epithelial responses
that LO may control or influence.
Address correspondence to: Joshua A.
Boyce, Hale Building for Transformative
Medicine, Room V, Fenwood
Road, Boston, Massachusetts , USA.
Phone: ..; Email: jboyce@rics.
bwh.harvard.edu.
