Defining the Role of Anti- and Pro-inflammatory Outcomes of Interleukin-6 in Mental Health

Interleukin-6 (IL-6) is a major cytokine that promotes anti- and pro-inflammatory outcomes by activating the membrane IL-6 receptor (IL-6R) or the soluble IL-6 receptor (sIL-6R). IL-6R and sIL-6R signaling engage the JAK1/2/3 targets and the downstream transcription of STAT1 and STAT3 family. In the brain, physiological IL-6 signaling preserves neurogenesis, neuronal differentiation, and neuroprotection against tissue injury, but IL-6 has been proposed as a biomarker for poor prognosis in several mental pathologies such as depressive disorders, schizophrenia, bipolar disorder, and autism. Physiological or pathological outcomes of IL-6 are related to its pleiotropic effects in the brain by microglia, astrocytes, neurons, and endothelial cells, and also by peripheral infiltrating macrophages or T lymphocytes. Notably, definition of anti- or pro-inflammatory profiles by IL-6 signaling in the brain are sensitive to the levels, cellular source, and targets of the IL-6 itself, as well as IL-6 receptor signaling, and its activation/inhibition ratio. We propose that a mutual IL-6 crosstalk between microglia, astrocytes, neurons, and endothelial cells defines the anti- and pro-inflammatory outcomes in the brain, modulating brain function. This review will describe the cellular, molecular and context-dependent signaling pathways that define anti- or pro-inflammatory profiles setting by IL-6 during physiological or pathological outcomes in the brain.