Cannabinoid receptor 2 is necessary to induce toll-like receptor-mediated microglial activation

The tight regulation of microglia activity is key for precise responses to potential threats, while uncontrolled and exacerbated microglial activity is neurotoxic. Microglial toll-like receptors (TLRs) are indispensable for sensing different types of assaults and triggering an innate immune response. Cannabinoid receptor 2 (CB2) signaling is a key pathway to control microglial homeostasis and activation, and its activation is connected to changes in microglial activity. We aimed to investigate how CB2 signaling impacts TLR-mediated microglial activation. Here, we demonstrate that deletion of CB2 causes a dampened transcriptional response to prototypic TLR ligands in microglia. Loss of CB2 results in distinct microglial gene expression profiles, morphology, and activation. We show that the CB2-mediated attenuation of TLR-induced microglial activation is mainly p38 MAPK-dependent. Taken together, we demonstrate that CB2 expression and signaling are necessary to fine-tune TLR-induced activation programs in microglia.

Automated summary

Tight regulation of microglial activity is crucial for precise responses to threats, as uncontrolled activity can be neurotoxic. Cannabinoid receptor 2 (CB2) signaling plays a key role in controlling microglial homeostasis and activation, impacting the response to Toll-like receptor (TLR) mediated activation. The deletion of CB2 leads to dampened transcriptional response and distinct gene expression profiles in microglia, influencing their activation programs.