Role of IL-18 in MI-Induced Myelopoiesis
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Date
2022-05
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The Ohio State University
Abstract
Interleukin-18 (IL-18), a prominent member of the IL-1 pro-inflammatory cytokine family, has been
found to be upregulated via inflammasome signaling post-myocardial infarction (MI), much like its
sibling cytokine IL-1β. Contemporary understanding of IL-1β far surpasses that of IL-18 in the
context of neutrophil signaling for myelopoiesis post-MI. IL-18 and IL-1β share a myriad of
characteristics ranging from analogous protein structure to undergoing the same inflammasome
processing. A pivotal study presented by Sreejit et al 2022 mechanistically detailed reverse
neutrophil migration and delivery of IL-1β to the bone marrow (BM) to upregulate myelopoiesis
post-MI.
The objective of this thesis is to explore the potential of IL-18 to be secreted and induce
myelopoiesis, similar to IL-1β. To address clinical relevance of this study, the CANTOS Trial
displayed promising therapeutic potential of IL-1β blockade in cardiovascular disease (CVD), thus
the information this study uncovers concerning IL-18 may have potential to be therapeutically
valuable.
This study first analyzed IL-18 compared against IL-1β secretion and mRNA expression in
inflammasome activated neutrophils, recapitulating previous findings regarding IL-1β secretion
from neutrophils and revealing novel finding about IL-18 secretion. mRNA expression of
inflammasome components and IL-18 and IL-1β was measured in activated neutrophils to
determine inflammasome activity as well as cytokine expression. The potential for IL-18 to induce
myelopoiesis in bone marrow derived stem cells was assessed using fluorescent labeling of newly
synthesized DNA. All assays were performed in vitro on murine cell cultures and their products.
Classical inflammasome priming and subsequent activation, with lipopolysaccharide (LPS) from
E. coli and Nigericin, produced upregulated IL-1β mRNA expression and secretion, but
unexpectedly failed to produce the same results with IL-18. Confirmations of assay efficacy were
performed to validate these results. Proliferaton was found to be highest in the unstimulated cells
compared to IL-18 and LPS stimulated cells demonstrating that IL-18 alone is not sufficient in
order to stimulate myelopoiesis.
IL-18 may exhibit a unique secretion and expression pattern compared to IL-1β. These results
also suggest that IL-18, isolated from other stimulating factors, is incapable of stimulating
myelopoiesis in an in vitro setting.