Inflammation adaptation is a major contributor to many acute and chronic inflammatory diseases. We will determine Toll-like receptor (TLR) signaling couples with miRNA and RNA-binding proteins to support inflammation phase shift from initiation to adaptation during sepsis acute inflammatory response. This proposal builds upon our discovery that both transcription and translation are silenced and independently regulated during acute sepsis inflammation. TLR-dependent signaling epigenetically represses transcription of a set of acute proinflammatory genes like TNF1 and IL-12, while activating transcription of genes encoding anti- inflammatory IkB1 and anti-microbial peptides. This reprogramming process requires de novo induction of RelB, which initiates assembly of a multicomponent complex of histone and DNA modifiers that convert euchromatin to facultative heterochromatin. Reversal of silent facultative heterochromatin to responsive euchromatin, however, restores mRNA levels but not protein synthesis of acute proinflammatory proteins. Based on our recent publications and preliminary data, we hypothesize that dysregulated TLR signal combine with regulatory RNA-binding motif protein 4 (RBM4) to disrupt mRNA translation of inflammatory genes, according to function. To do this, Aim 1 will define the pathway that modulates RBM4 activity to promote inflammation adaptation, and Aim 2 will determine how RBM4 represses translation during TLR4-dependent adaptation. We predict finding the molecular regulator that switches sepsis inflammation from initiation to adaptation, which may help in designing pathway-specific therapies.
Acute inflammation incited by sepsis or trauma has a major health impact, with extensive mortality and limited effective treatment options. Since there is no successful treatment for sepsis during the inflammation adaptation phase, our research could inform novel therapies. As part of the NIGMS strategic plan, we analyze fundamental mechanisms that traverse multiple organ systems.
|McClure, Clara; Brudecki, Laura; Yao, Zhi Q et al. (2015) Processing Body Formation Limits Proinflammatory Cytokine Synthesis in Endotoxin-Tolerant Monocytes and Murine Septic Macrophages. J Innate Immun 7:572-83|
|El Gazzar, Mohamed (2014) microRNAs as potential regulators of myeloid-derived suppressor cell expansion. Innate Immun 20:227-38|
|Brudecki, Laura; Ferguson, Donald A; McCall, Charles E et al. (2013) Mitogen-activated protein kinase phosphatase 1 disrupts proinflammatory protein synthesis in endotoxin-adapted monocytes. Clin Vaccine Immunol 20:1396-404|
|Brudecki, Laura; Ferguson, Donald A; McCall, Charles E et al. (2013) MicroRNA-146a and RBM4 form a negative feed-forward loop that disrupts cytokine mRNA translation following TLR4 responses in human THP-1 monocytes. Immunol Cell Biol 91:532-40|