Runt-Related Transcription Factor 1 Regulates LPS-Induced Acute Lung Injury via NF-κB Signaling

Abstract

Runt-related transcription factor 1 (RUNX1), a transcription factor expressed in multiple organs, plays important roles in embryonic development and hematopoiesis. Although RUNX1 is highly expressed in pulmonary tissues, its roles in lung function and homeostasis are unknown. We sought to assess the role of RUNX1 in lung development and inflammation after LPS challenge. Expression of RUNX1 was assessed in the developing and postnatal lung. RUNX1 was conditionally deleted in pulmonary epithelial cells. Pulmonary maturation was evaluated in the developing and postnatal lung, and lung inflammation was investigated in adult mice after LPS challenge. Interactions between RUNX1 and inflammatory signaling via NF-κB-IkB kinase β were assessed in vitro. RUNX1 was expressed in both mesenchymal and epithelial compartments of the developing and postnatal lung. The RUNX1 gene was efficiently deleted from respiratory epithelial cells producing Runx1 mice. Although lung maturation was delayed, Runx1 mice survived postnatally and subsequent growth and maturation of the lung proceeded normally. Increased respiratory distress, inflammation, and proinflammatory cytokines were observed in the Runx1-deleted mice after pulmonary LPS exposure. RUNX1 deletion was associated with the activation of NF-κB in respiratory epithelial cells. RUNX1 was required for the suppression of NF-κB signaling pathway via inhibition of IkB kinase β in in vitro studies. RUNX1 plays a critical role in the lung inflammation after LPS-induced injury.

Runx1 negatively regulates inflammatory cytokine production by neutrophils in response to Toll-like receptor signaling

“…This model is distinct from previously reported mechanisms in macrophages and lung epithelial cells whereby RUNX1 dampens TLR4 signaling through direct interaction between the RUNX1 protein with either the p50 subunit of NF-kB or the inhibitor of IkB kinase. 8,26,27 The upregulation of TLR pathway components in upstream Runx1 KO neutrophil HPs suggests that RUNX1 may regulate inflammatory signaling during neutrophil differentiation in a cell-autonomous manner. However, noncell-autonomous effects could also contribute to an inflammatory state either in neutrophil HPs or in neutrophils themselves.…”

“…In vivo deletion of RUNX1 in lung alveolar epithelial cells using a surfactant-associated protein C-driven Cre increased the susceptibility of mice to lipopolysaccharide (LPS)-induced acute lung injury. 8 The mechanism by which RUNX1 represses inflammation in lung epithelial cells is through dampening toll-like receptor 4 (TLR4) signaling. TLR4 is the membrane receptor for LPS, a component of gram-negative bacterial cell walls.…”

“…RUNX1 inhibited the NF-kB arm of the MyD88-TIRAP pathway in lung epithelial cells by binding to the inhibitor of NF-kB (IkBa) kinase in the cytoplasm, which dampened the phosphorylation and degradation of IkBa and increased retention of NF-kB in the cytoplasm. 8 Studies in humans suggest a role for RUNX1 in regulating autoimmunity and inflammation. Regulatory single nucleotide polymorphisms in RUNX binding sites in several genes have been linked to psoriasis, systemic lupus erythematosus, and rheumatoid arthritis.…”

Chelerythrine Attenuates the Inflammation of Lipopolysaccharide-Induced Acute Lung Inflammation Through NF-κB Signaling Pathway Mediated by Nrf2

“…et al, 2017 ). Activated NF-κB translocates into the nucleus where it triggers the transcription of specific genes such as TNF-α, IL-1β, and IL-6 ( Tang et al, 2017 ). NF-κB binding sequences have also been identified in proinflammatory genes such as iNOS and COX-2 ( Zhang et al, 2018 ).…”

RUNX1 Mutations in Inherited and Sporadic Leukemia

“…Runx3 knockout mice exhibit spontaneous colitis and lung inflammation, in part due to dysregulated TGF-β signaling (Brenner et al, 2004 ; Fainaru et al, 2004 ). RUNX1 also negatively regulates inflammatory signaling in the lung (Tang et al, 2017 ). Deletion of Runx1 in lung epithelium resulted in constitutive activation of NF-κB pro-inflammatory signaling and increased susceptibility to LPS-induced acute lung injury in vivo (Tang et al, 2017 ).…”