Bid regulates the immunological profile of murine microglia and macrophages

Abstract

Apoptosis is a controlled cell-death process mediated inter alia by proteins of the Bcl-2 family. Some proteins previously shown to promote the apoptotic process were found to have nonapoptotic functions as well. Microglia, the resident immune cells of the central nervous system, respond to brain derangements by becoming activated to contend with the brain damage. Activated microglia can also undergo activation-induced cell death. Previous studies have addressed the role of core apoptotic proteins in the death process, but whether these proteins also play a role or not in the activation process is not been reported. Here we explore the effect of the BH3-only protein Bid on the immunological features of microglia and macrophages. Our results showed that Bid regulates both the phagocytotic activities and the inflammatory profiles of these cells. Deficiency of Bid attenuated the phagocytotic activity of primary microglia and peritoneal macrophages. It also changed the expression profile of distinct inflammation-related genes in lipopolysaccharide-activated microglia and peritoneal macrophages in vitro and in an in vivo sepsis-like paradigm. Notably, similar changes followed downregulation of Bid in the N9 microglial cell line. Cell death could not be detected in any of the systems examined. Our findings demonstrate that Bid can regulate the immunological profiles of activated microglial and macrophages, via a novel nonapoptotic activity. In view of the critical role of these cells in various pathologies, including acute and chronic brain insults, our findings suggest that impairments in Bid expression may contribute to these pathologies also via a nonapoptotic activity.

The BCL-2 family protein Bid is critical for pro-inflammatory signaling in astrocytes

“…These results are also in 10 agreement with a study showing a non-apoptotic, Bid-dependent activation of COX-II in 11 fibroblasts exposed to alkylating agents (Luo et al, 2010). Recently, it was found that bid-12 deficient macrophages and microglia also exhibited an impaired ability of pro-inflammatory 13 cytokine production (Mayo et al, 2011). It is therefore conceivable that Bid plays a key role 14 in the supply of pro-inflammatory cytokines from both microglia and astroglia (Nagai et al,15 2007), thereby amplifying inflammation (Yamanaka et al, 2008).…”

“…However, in most cell types, this direct activation 19 pathway is not sufficient to activate apoptosis, and an amplification loop is required for cell 20 death execution that involves the BH3-only protein Bid, and hence engages the 21 mitochondrial apoptosis pathway (Lovell et al, 2008;Luo et al, 1998 (Guegan et al, 2002). Interestingly, Bid was recently implicated in the production of pro-25 inflammatory cytokines in macrophages and microglia (Mayo et al, 2011) and was 26 reported to be involved in the activation of the transcription factor nuclear factor-κB (NF-1 κB) in response to stimulation of pattern recognition receptors in intestinal epithelial cells, 2 independent of its direct apoptosis-regulating function (Yeretssian et al, 2011). Therefore, 3 in the present study we sought to clarify the role of Bid in the context of neurodegeneration 4 and neuroinflammation relevant to ALS.…”

Extracellular TDP‐43 aggregates target MAPK/MAK/MRK overlapping kinase (MOK) and trigger caspase‐3/IL‐18 signaling in microglia

“…Mixed glial cultures were prepared from cerebral cortices of 1‐ to 3‐d‐old C57BL/6 male mice (University of Seville Animal Core Facility), and microglia were isolated by mild trypsinization as previously described (30), with minor modifications as follows. Sixteen mouse brains were used per culture batch.…”

Dendritic Polyglycerol Sulfate Inhibits Microglial Activation and Reduces Hippocampal CA1 Dendritic Spine Morphology Deficits

“…These cells were selected because it is known that they have many properties similar to primary microglia cultures, which was confirmed in a previous publication. 47,56 Seeing that dPGS was nontoxic in microglia at a concentration of 100 nM (MTT assay, trypan blue exclusion assay and Hoechst 33342 labeling of cell nuclei, see below), we investigated if this lack of toxicity could be explained by their inability to enter the cells and only temporarily bind to plasma membrane putative selectin receptors. 20,53 For this we used dPGS-Cy5 and the control triglycerol-Cy5 (TG-Cy5) and untreated cells (controls for autofluorescence).…”