Cannabinoid receptor 2 is necessary to induce toll‐like receptor‐mediated microglial activation
Nico Reusch, Kishore Aravind Ravichandran, Bolanle Fatimat Olabiyi, Joanna Agnieszka Komorowska‐Müller, Jan N. Hansen, Thomas Ulas, Marc Beyer, Andreas Zimmer, Anne‐Caroline Schmöle
Abstract
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.