Histone deacetylase 2 (HDAC2) attenuates lipopolysaccharide (LPS)-induced inflammation by regulating PAI-1 expression

Abstract

BackgroundSepsis is a life-threatening organ dysfunction caused by dysregulated host response to infection, and is primarily characterized by an uncontrolled systemic inflammatory response. In the present study, we developed an effective adjunct therapy mediated by a novel mechanism, to attenuate overt inflammation. LPS-treated macrophages were adopted as an in vitro model of endotoxin-induced inflammation during sepsis. Experiments were carried out using primary mouse peritoneal macrophages and the murine macrophage cell line RAW264.7, to elucidate the mechanisms by which HDAC2 modulates endotoxin-induced inflammation.ResultsResults revealed that PAI-1, TNF, and MIP-2 expression were inhibited by theophylline, an HDAC2 enhancer, in a RAW macrophage cell line, following LPS-induced inflammation. Thus, HDAC2 plays an important role in immune defense by regulating the expression of inflammatory genes via the c-Jun/PAI-1 pathway. During LPS-induced inflammation, overexpression of HDAC2 was found to inhibit PAI-1, TNF, and MIP-2 expression. Following LPS stimulation, HDAC2 knockdown increased nuclear translocation and DNA binding of c-Jun to the PAI-1 gene promoter, thereby activating PAI-1 gene transcription. Furthermore, inhibition of PAI-1 by TM5275 alone or in combination with theophylline notably suppressed TNF and MIP-2 expression.ConclusionHDAC2 can attenuate lipopolysaccharide-induced inflammation by regulating c-Jun and PAI-1 expression in macrophages.

Incorporation of dynamic segmented neutrophil-to-monocyte ratio with leukocyte count for sepsis risk stratification

“…The dynamic tool is better than simple SOFA score on ICU admission. Multiple organ dysfunction is complicated and associated with organ–organ interaction 30,31 . In our study, we found that WBC count alone on day 1 cannot differentiate survival from non-survival.…”

Ventilator Dependence Risk Score for the Prediction of Prolonged Mechanical Ventilation in Patients Who Survive Sepsis/Septic Shock with Respiratory Failure

“…Sepsis is a life-threatening organ dysfunction caused by a disproportionate host response to infection and it involves complex mechanisms 22 . During sepsis, platelet numbers decrease due to increased platelet destruction.…”

Covid-19: Perspectives on Innate Immune Evasion

“…The blockade of interferon signaling, described above, would limit ISG expression in macrophages, including cytokine-induced MHC II expression (139). The SARS-CoV-2 protein Nsp5 interacts with the epigenetic regulator histone deacetylase 2 (HDAC2), which regulates MHC II expression and cytokine production (138,140,141). While it is unknown whether SARS-CoV-2 inhibits or enhances HDAC2 activity, this interaction indicates a potential direct modulation of the cytokine storm and antigen presentation.…”