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Principal Investigator: Irina G. Luzina
Organization: BALTIMORE VA MEDICAL CENTER
Fiscal Year: 2024
Funding agency: Veterans Affairs
Interleukin (IL)-33 and its receptor, ST2, centrally control a remarkable variety of inflammatory and fibrotic
diseases. The IL-33 – ST2 axis relies mostly on the proteolytically mature form of IL-33 cytokine (MIL33), with
less attention usually devoted to the full-length precursor (FLIL33), which is a nuclear factor. The MIL33 – ST2
axis serves diverse functions, among which one of the most prominent is induction of the Th2 phenotype, with
an overt elevation of IL-4, IL-5, and IL-13, leading to eosinophilia, mucus production, and clinical manifestation
of allergy. It remains unclear how the MIL33 – ST2 pathway, while certainly contributing to inflammation and
fibrosis, mediates its proinflammatory and profibrotic effects without always eliciting the Th2 phenotype. Our
preliminary data strongly suggest that IL-33, particularly in its FLIL33 form, may promote inflammation and
fibrosis in an ST2-independent fashion, and reciprocally, ST2 may control inflammation and fibrosis without
requiring IL-33. Thus, we proposed, for the first time, that IL-33 and ST2 may contribute to inflammation and
fibrosis in an “off-axis” fashion. FLIL33 behaves distinctly from MIL33. Some earlier studies suggested that as
a basally and inducibly expressed nuclear factor, FLIL33 modulates inflammatory responses, wound healing,
chromatin stability, and transcriptional regulation in a non-Th2 and receptor-independent manner. Yet, the
pathophysiology of the understudied FLIL33 requires more attention in general and is nearly completely
unknown in fibrosis specifically. Our published and preliminary data suggest that: FLIL33 but not MIL33
potentiates fibrosis without inducing the Th2 phenotype; such distinct effect is partially mediated by ST2 and
also occurs in the absence of ST2; FLIL33 acts so at the levels of both transcriptional and post-transcriptional
regulation; ST2 by itself controls fibrosis; and such regulation involves IL-9.
Based on these findings, the Hypothesis of this study is that in addition to the commonly acknowledged role of
the MIL33 – ST2 axis, FLIL33 contributes to fibrosis both with and without engaging ST2, through both
transcriptional and post-transcriptional regulation, and that ST2 itself may regulate fibrosis through a
mechanism that in part involves IL-9. To challenge this hypothesis, the following Specific Aims will be pursued.
Aim 1 is to define ST2-independent, Th2-independent, post-transcriptional, mechanisms through which full-
length IL-33 potentiates fibrosis. Aim 2 is to define ST2-dependent, Th2-independent, transcriptional,
mechanisms through which full-length IL-33 potentiates fibrosis. Aim 3 is to determine the role of IL-9 in
controlling fibrosis in an ST2-dependent fashion and identify the mechanisms through which both full-length
and mature IL-33 forms attenuate IL-9. A successful completion of these studies will form the basis for better
therapeutic targeting of IL-33 and ST2 is inflammatory and fibrotic diseases. Inflammation and fibrosis are
distinct yet frequently co-occurring processes contributing to a remarkably broad variety of diseases of every
organ and tissue. The inflammatory fibrotic diseases affect the general population; but are particularly
prevalent in Veterans because of their military service-related exposures as well as their often-unhealthy post-
service lifestyles. The central regulatory role of interleukin (IL)-33 as a potent inducer of inflammation and
fibrosis has been solidly established, but the molecular mechanisms of IL-33 biology and pathology are not
fully understood - a limitation that will be addressed by the planned work based on our innovative, paradigm-
shifting, hypothesis. Importantly, both FLIL33 and MIL33 become pathophysiologically engaged under stress,
but IL-33-null mice have no noticeable basal phenotype, suggesting that depletion of IL-33 levels and/or
attenuation of its functions are a safe therapeutic approach. Altogether, the results of this work will uncover
novel aspects of IL-33 biology and form the basis for the development of novel, precise therapeutic modalities
for Veterans with inflammatory and fibrotic diseases.
Terms: <Address><Adipose tissue><Affect><Allergy><Armed Forces Personnel><Attention><Attenuated><B Cell Differentiation Factor I><B cell growth factor><B cell growth factor 2><B-Cell Differentiation Factor-1><B-Cell Growth Factor-1><B-Cell Growth Factor-I><B-Cell Growth Factor-II><B-Cell Proliferating Factor><B-Cell Stimulating Factor><B-Cell Stimulating Factor-1><B-Cell Stimulation Factor-1><B-Cell Stimulatory Factor-1><BCDF-1><BCGF><BCGF-1><BCGF-II><BCGF2><BCSF 1><BSF-1><BSF1><Binetrakin><Biology><Body Tissues><Chromatin><Cicatrix><Clinical><Complication><Data><Development><Disease><Disorder><Dysfunction><Eo-CSF><Eosinophil Differentiation Factor><Eosinophilia><Fatty Tissue><Fibrosis><Functional disorder><Future><Gene Transcription><General Population><General Public><Genetic Transcription><HP40><Heart><Homolog of Mouse T Cell and Mast Cell Growth Factor 40><Human><Hypersensitivity><IL-13><IL-4><IL-5><IL-9><IL13><IL4 Protein><IL9 Protein><IgA enhancing factor><Inflammation><Inflammatory><Inflammatory Response><Innovative Therapy><Interleukin 5 Precursor><Interleukin 9 Precursor><Interleukin-13><Interleukin-4><Interleukin-4 Precursor><Interleukin-5><Interleukin-9><Interleukins><KO mice><Kidney><Kidney Urinary System><Knock-out Mice><Knockout Mice><Laboratories><Length><Life Style><Lifestyle><Liver><Lung><Lung Respiratory System><Lymphocyte Stimulatory Factor 1><MCGF-2><Mast Cell Growth Factor-2><Mediating><Military><Military Personnel><Modality><Modeling><Modern Man><Molecular><Mucous body substance><Mucus><Nuclear><Null Mouse><Organ><Pathology><Pathway interactions><Patients><Peritoneum><Phenotype><Physiopathology><Post-Transcriptional Control><Post-Transcriptional Regulation><Process><Production><Publishing><QOL><Quality of life><RNA Expression><Receptor Protein><Regulation><Research><Role><Scars><Services><Skeletal Muscle><Skin><Solid><Stress><T cell replacing factor><T-Cell Growth Factor 2><T-Cell Growth Factor P40><T-Cell Replacing Factor><T-Cell/Mast Cell Growth Factor p40><Therapeutic><Time><Tissues><Transcription><Transcription Regulation><Transcriptional Control><Transcriptional Regulation><Veterans><Voluntary Muscle><Work><Wound Repair><adipose><attenuate><attenuates><attenuation><cell type><cytokine><developmental><hepatic body system><hepatic organ system><inflammatory modulation><innovate><innovation><innovative><insight><military population><military service><mucous><novel><p40 Cytokine><p40 Protein><pathophysiology><pathway><post-transcriptional gene regulation><posttranscriptional><posttranscriptional control><posttranscriptional regulation><pulmonary><receptor><renal><social role><therapeutic target><white adipose tissue><wound healing><wound recovery><wound resolution><yellow adipose tissue>