BCL6 attenuates renal inflammation via negative regulation of NLRP3 transcription

Abstract

Renal inflammation contributes to the pathogeneses of hypertension. This study was designed to determine whether B-cell lymphoma 6 (BCL6) attenuates renal NLRP3 inflammasome activation and inflammation and its underlying mechanism. Male spontaneously hypertensive rats (SHR) and Wistar-Kyoto rats (WKY) were used in the present study. Angiotensin (Ang) II or lipopolysaccharides (LPS) was used to induce inflammation in HK-2 cells, a human renal tubular epithelial (RTE) cell line. NLRP3 inflammasome was activated and BCL6 was downregulated in the kidneys of SHR. Either Ang II or LPS suppressed BCL6 expression in HK-2 cells. BCL6 overexpression in HK-2 cells attenuated Ang II-induced NLRP3 upregulation, inflammation and cell injury. The inhibitory effects of BCL6 overexpression on NLRP3 expression and inflammation were also observed in LPS-treated HK-2 cells. BCL6 inhibited the NLRP3 transcription via binding to the NLRP3 promoter. BCL6 knockdown with shRNA increased NLRP3 and mature IL-1β expression levels in both PBS- or Ang II-treated HK-2 cells but had no significant effects on ASC, pro-caspase-1 and pro-IL-1β expression levels. BCL6 overexpression caused by recombinant lentivirus expressing BCL6 reduced blood pressure in SHR. BCL6 overexpression prevented the upregulation of NLRP3 and mature IL-1β expression levels in the renal cortex of SHR. The results indicate that BCL6 attenuates Ang II- or LPS-induced inflammation in HK-2 cells via negative regulation of NLRP3 transcription. BCL6 overexpression in SHR reduced blood pressure, NLRP3 expression and inflammation in the renal cortex of SHR.

Bcl6 knockdown aggravates hypoxia injury in cardiomyocytes via the P38 pathway

“…The imbalance between oxidants and antioxidants (oxidative stress) favors the accumulation of oxidants. This imbalance results from increased ROS production and decreased ROS scavenging, and leads to protein, lipid, and DNA damage in cardiomyocytes (Chen et al, ). Increased ROS levels also increase proteolysis of excitation‐contraction coupling protein (Ayoub et al, ).…”

“…By targeting diverse factors, including transcription factors such as signal transducers and activators of transcription (STAT3 and STAT5B), and microRNA interaction, Bcl6 contributes to the progression of various types of cancer (Hatzi and Melnick, ; Wei et al, ; Cardenas et al, ). Bcl6 can also relieve renal inflammation by negatively regulating nucleotide‐binding domain, leucine‐rich‐containing family, pyrin domain‐containing‐3 (NLRP3) inflammasomes (Chen et al, ). Bcl6 also promotes the polarization of M2‐like macrophages and protects macrophages against oxidative stress and apoptosis (Jia et al, ).…”

Aloe emodin relieves Ang II-induced endothelial junction dysfunction via promoting ubiquitination mediated NLRP3 inflammasome inactivation

“…For example, BCL6 suppresses the NLRP3 transcription through binding to the NLRP3 promoter. 29 TRIM31 as an E3 ubiquitin ligase, accelerates the degradation of NLRP3 via promoting K48linked polyubiquitination. 30 Pellino2, which is dependent on Pellino2…”

“…Several mechanisms about inhibiting the NLRP3 protein have been reported. For example, BCL6 suppresses the NLRP3 transcription through binding to the NLRP3 promoter 29 . TRIM31 as an E3 ubiquitin ligase, accelerates the degradation of NLRP3 via promoting K48‐linked polyubiquitination 30 .…”

Transcriptional Regulation of Inflammasomes

“…Besides NF-κB and NR1D1, direct binding of several TFs on the NLRP3 promoter have been reported with either negative or positive impact on NLRP3 expression. Down-regulation of NLRP3 expression is controlled by the aryl hydrocarbon receptor (AhR) [47] and by B cell lymphoma 6 (BCL6), a transcriptional repressor that antagonizes NF-κB-mediated gene transcription [48]. AhR is a ligand-activated TF binding numerous environmental contaminants (e.g.…”