Adaptive immune signaling at the meningeal barrier: neuroimmune interactions underlying stress-induced mood disruption
Stacey L. Kigar1, Samuel J. Listwak1, Donghyun Kim1, Virginia Sun1,2, Abdel Elkahloun3, Miles Herkenham1
1Section on Functional Neuroanatomy - National Institute of Mental Health, Bethesda, MD; 2Massachussettes Institute of Technology, Boston, MA; 3Microarray Core - National Human Genome Research Institute, Bethesda, MD
Major depressive disorder (MDD) is strongly correlated with increased peripheral inflammation, but basic mechanisms by which the immune system influences the brain under these conditions remain largely unknown. The blood brain barrier (BBB) in particular prevents free exchange of peripheral immune signals with the central nervous system (CNS); however, relatively high numbers of CD4+ T (Th) cell lymphocytes extravasate across the BBB under homeostatic conditions to gain direct access to the CNS via cerebrospinal fluid (CSF). While Th cells have access to the CNS from within this space, there is no evidence to suggest they reside in healthy brain parenchyma and must therefore transmit information to the brain indirectly. Greater understanding of this process is critical to exploit peripheral immunity for MDD treatment.
I focus on the meninges—which envelop the brain, contain the BBB, and confine the CSF—as a key interface between the CNS and peripheral immune system. My hypothesis, supported by flow cytometric, bioinformatic, and IHC analyses, is that Th cells are recruited to the meninges to facilitate repair due to depression-induced damage; once inside, they release signaling factors which alter neurobiology. To test this idea, I use chronic social defeat (CSD) stress in mice, which reliably induces depressive- and anxious-like behavior and leads to elevated levels of peripheral inflammation, consistent with MDD. I have observed increased infiltration of T cells into the meninges of CSD-stressed animals, accompanied by increased peripheral skewing of T cells towards a pro-inflammatory phenotype. I am currently doing multicolor flow cytometry and single cell RNA sequencing analysis to determine which Th cell variants are most closely associated with CSD stress, what resident meningeal cells are responsible for their recruitment, and what CNS-mediated events precipitate an immune reaction. Candidates generated will be further studied for their role in inducing or alleviating the depressive effects of CSD stress.