We study how resident cells of the central nervous system coordinate specialized immune responses to

infection and injury.

RIPK signaling in neurons during West Nile virus infection drives chemokine expression and subsequent recruitment of inflammatory cells into the infected CNS. 

(see Daniels et al, Cell, 2017)

Immunogenic cell death signaling at the

blood-brain barrier

 

     Infection and injury of the central nervous system (CNS) induce programmed cell death responses in a variety of neural cell types. In particular, the canonical form of programmed cell death, apoptosis, has been extensively studied as a source of tissue pathology and immunoregulation during CNS disease states. However, roles for nonapoptotic cell death programs, such as necroptosis, during neuroinflammatory disease remain poorly understood.

     Using mouse and cell culture models of neuroinvasive viral infection and traumatic injury, we are examining roles for the necroptotic kinases RIPK1 and RIPK3 at the blood-brain barrier (BBB), a multicellular interface that tightly regulates the trafficking of immune cells into the CNS. Ongoing questions include: 1) Are cells of the BBB susceptible to necroptosis during infection and injury? 2) Does RIPK signaling at the BBB exhibit distinct cell death-dependent and -independent outcomes that vary by stimulus and cell type? and 3) How does BBB RIPK signaling shape protective vs. pathologic immune responses across the CNS?

Immunologic heterogeneity of the CNS

     The CNS is comprised of a number of highly specialized cell types, including neurons, glia, vascular endothelia, and others. Moreover, each of these individual cell types are further specialized across the various anatomical regions of the CNS. The extensive cell-type and regional heterogeneity of the CNS underlies this organ system’s incredibly complex functional capacity. In addition, our work and others’ have shown that the CNS also displays considerable heterogeneity in its immune responses across cell types and regions, though the determinants of immunologic heterogeneity in the CNS are mysterious. Our lab seeks to understand how unique functional, developmental, morphological, and evolutionary features of CNS cell types and antomical regions shape inflammatory responses to infection and traumatic injury. 

RNAseq reveals distinct interferon-stimulated transcriptional programs in human astrocytes from cerebral cortex (CTX) and cerebellum (CBL).

(see Daniels et al, JCI, 2017)

© 2020 Brian Daniels.