GM-CSF Promotes the Survival of Peripheral-Derived Myeloid Cells in the Central Nervous System for Pain-Induced Relapse of Neuroinflammation

Abstract

We recently discovered a (to our knowledge) new neuroimmune interaction named the gateway reflex, in which the activation of specific neural circuits establishes immune cell gateways at specific vessel sites in organs, leading to the development of tissue-specific autoimmune diseases, including a multiple sclerosis (MS) mouse model, experimental autoimmune encephalomyelitis (EAE). We have reported that peripheral-derived myeloid cells, which are CD11b+MHC class II+ and accumulate in the fifth lumbar (L5) cord during the onset of a transfer model of EAE (tEAE), play a role in the pain-mediated relapse via the pain-gateway reflex. In this study, we investigated how these cells survive during the remission phase to cause the relapse. We show that peripheral-derived myeloid cells accumulated in the L5 cord after tEAE induction and survive more than other immune cells. These myeloid cells, which highly expressed GM-CSFRα with common β chain molecules, grew in number and expressed more Bcl-xL after GM-CSF treatment but decreased in number by blockade of the GM-CSF pathway, which suppressed pain-mediated relapse of neuroinflammation. Therefore, GM-CSF is a survival factor for these cells. Moreover, these cells were colocalized with blood endothelial cells (BECs) around the L5 cord, and BECs expressed a high level of GM-CSF. Thus, GM-CSF from BECs may have an important role in the pain-mediated tEAE relapse caused by peripheral-derived myeloid cells in the CNS. Finally, we found that blockade of the GM-CSF pathway after pain induction suppressed EAE development. Therefore, GM-CSF suppression is a possible therapeutic approach in inflammatory CNS diseases with relapse, such as MS.

Identifying circRNA–miRNA–mRNA Regulatory Networks in Chemotherapy-Induced Peripheral Neuropathy

“…Our results showed that both detected and predicted mRNAs were enriched in immune and inflammatory processes and pathways. Simultaneously, the overlapping mRNAs were enriched in the regulation of myeloid cell differentiation, response to cycloheximide, and cellular response to interleukin-1, which were associated with neuroimmune and neuropathic pain [ 29 , 30 , 31 ]. KEGG pathway analysis also illustrated that overlapping mRNAs were enriched in the p53 signaling pathway, natural killer (NK) cell-mediated cytotoxicity, and TNF signaling pathway, which could modulate the development of pain [ 32 , 33 , 34 ].…”

The Mechanisms of Altered Blood–Brain Barrier Permeability in CD19 CAR T–Cell Recipients

“…TNF-α, in turn, increases the expression of leukocyte adhesion molecules, such as intercellular adhesion molecule 1 (ICAM-1) and vascular cell adhesion molecule 1 (VCAM-1), which enable the attachment and migration of stimulated monocytes across the BBB [ 22 ]. Once trafficked across the BBB, the GM-CSF–stimulated monocytes mature into macrophages and secrete reactive oxygen species that damage the cytoskeleton of neurons and glial cells [ 23 ]. In a preclinical study by Sterner et al, a mouse model implanted with leukemic blasts and treated with human CD19 CAR T cells developed hunched posture and motor weakness, with elevated serum levels of GM-CSF and increased contrast enhancement on brain magnetic resonance images (MRIs), compatible with neurotoxicity.…”