Microglia, astrocytes, and neurons all contribute immune signaling responses in traumatic brain injury and Alzheimer’s disease. My laboratory interrogates signaling mechanisms of brain injury and disease using a combination of targeted phospho-proteomic and cytokine signaling assays and gene expression network analysis in concert with mouse and in vitro model systems. In this talk, I will highlight our recent findings implicating neuronal p38 MAPK immune signaling as a driver of traumatic brain injury and our ongoing work implicating hyperactivated microglial MAPK/ERK signaling in Alzheimer’s disease. I will highlight our recently established tools for interrogating immune signaling from individual cell types using transgenic TurboID-based native state proteomics. These new tools combined with omics-based profiling hold the potential to unlock critical immune-based disease mechanisms and novel immune-targeting therapies.