The central role of IL-33/IL-1RL1 pathway in asthma: From pathogenesis to intervention

https://doi.org/10.1016/j.pharmthera.2021.107847Get rights and content
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Abstract

Interleukin-33 (IL-33), a member of the IL-1 family, and its cognate receptor, Interleukin-1 receptor like-1 (IL-1RL1 or ST2), are susceptibility genes for childhood asthma. In response to cellular damage, IL-33 is released from barrier tissues as an ‘alarmin’ to activate the innate immune response. IL-33 drives type 2 responses by inducing signalling through its receptor IL-1RL1 in several immune and structural cells, thereby leading to type 2 cytokine and chemokine production. IL-1RL1 gene transcript encodes different isoforms generated through alternative splicing. Its soluble isoform, IL-1RL1-a or sST2, acts as a decoy receptor by sequestering IL-33, thereby inhibiting IL1RL1-b/IL-33 signalling. IL-33 and its receptor IL-1RL1 are therefore considered as putative biomarkers or targets for pharmacological intervention in asthma. This review will provide an overview of the genetics and biology of the IL-33/IL-1RL1 pathway in the context of asthma pathogenesis. It will discuss the potential and complexities of targeting the cytokine or its receptor, how genetics or biomarkers may inform precision medicine for asthma targeting this pathway, and the possible positioning of therapeutics targeting IL-33 or its receptor in the expanding landscape of novel biologicals applied in asthma management.

Keywords

Asthma
IL-1RL1
IL-33
Immune cells
Epithelial cells
Genetics
Pharmacotherapy

Abbreviations

A disintegrin and metalloproteinase domain-containing protein 33
ADAM33
Activator protein-1
AP-1
Airway Hyperresponsiveness
AHR
Airway Smooth Muscle Cells
ASMCs
Alternaria alternata
ALT
Amphiregulin
AREG
Atopic dermatitis
AD
Bronchoalveolar lavage fluid
BALF
c-Jun N-terminal kinase
JNK
Carcinoma Cell Line
CCL
Damage Associated Molecular Pattern
DAMP
Dendritic cells
DCs
Early-Associated-Response
EAR
Expression quantitative trait loci
eQTL
Extracellular Receptor Kinase
ERK
Forced Expiratory Volume in one second
FEV1
GATA Binding Protein 1
GATA 1
Genome-Wide Association Study
GWAS
Granulocyte-macrophage colony-stimulating factor
GM-CSF
Histone 2A - Histone 2B
H2A-H2B
Histone-lysine N-methyltransferase
SUV39H1
IKappaB Kinase
IĸB
Immunoglobulin E
IgE
Inhaled Corticosteroids
ICS
Interferon gamma
INFγ
Interleukin 1 receptor accessory protein
IL-1RAcP
Interleukin 1 Receptor Like 1
IL-1RL1
Interleukin - 33
IL-33
Interleukin -
IL-
Interleukin receptor associated kinases
IRAK1/4
Invariant natural killer T
iNKT
Janus Kinase pathway
JAK
Late-Associated-Response
LAR
Linkage Disequilibrium
LD
Long-acting beta-adrenoceptor agonist
LABA
Major histocompatibility complex
MHC
mammalian target of rapamycin
mTOR
Mast cells
MCs
MyD88-adapter-like
MAL1
Myeloid differentiation primary response 88
MyD88
N-acetylglucosamine
NAG
Natural Killer cells
NKs
NLR family pyrin domain containing 3 - nucleotide-binding oligomerization domain
NLRP3-NOD
Nuclear Factor Kappa-light-chain-enhancer of activated B cells
NF-κB
Nuclear Factor-High Endothelial Venules
NF-HEV
phosphoinositide 3-kinase
PI3k
Protein quantitative trait loci
pQTL
Regulatory T cells
Treg
Reticular Basement Membrane
RBM
Short-acting beta-adrenoceptor agonist
SABA
Signal Transducer And Activator Of Transcription 5A
STAT5A
Single Ig IL-1-related receptor
SIGIRR
Single nucleotide polymorphisms
SNP
Stem cells antigen-1
Sca-1
T helper 2 lymphocyte
Th2
T helper 17 cells
Th17
T-cell receptor
TCR
The Toll/interleukin-1 receptor
TIR
Thymic stromal lymphopoietin
TSLP
Toll/Interleukin-1 receptor 8
TIR8
TRAF6
Tumor necrosis factor receptor (TNFR)-associated factor 6, TRAF6
Tumour Necrosis Factor alpha
TNF-α
Type 2 innate lymphoid cells
ILC2
Type 2
T2

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