The emerging neuroimmune hypothesis of bipolar disorder: An updated overview of neuroimmune and microglial findings

Bipolar disorder (BD) is a severe and multifactorial disease, with onset usually in young adulthood, which follows a progressive course throughout life. Replicated epidemiological studies have suggested inflammatory mechanisms and neuroimmune risk factors as primary contributors to the onset and development of BD. While not all patients display overt markers of inflammation, significant evidence suggests that aberrant immune signaling contributes to all stages of the disease and seems to be mood phase dependent, likely explaining the heterogeneity of findings observed in this population. As the brain's immune cells, microglia orchestrate the brain's immune response and play a critical role in maintaining the brain's health across the lifespan. Microglia are also highly sensitive to environmental changes and respond to physiological and pathological events by adapting their functions, structure, and molecular expression. Recently, it has been highlighted that instead of a single population of cells, microglia comprise a heterogeneous community with specialized states adjusted according to the local molecular cues and intercellular interactions. Early evidence has highlighted the contribution of microglia to BD neuropathology, notably for severe outcomes, such as suicidality. However, the roles and diversity of microglial states in this disease are still largely undermined. This review brings an updated overview of current literature on the contribution of neuroimmune risk factors for the onset and progression of BD, the most prominent neuroimmune abnormalities (including biomarker, neuroimaging, ex vivo studies) and the most recent findings of microglial involvement in BD neuropathology. Combining these different shreds of evidence, we aim to propose a unifying hypothesis for BD pathophysiology centered on neuroimmune abnormalities and microglia. Also, we highlight the urgent need to apply novel multi-system biology approaches to characterize the diversity of microglial states and functions involved in this enigmatic disorder, which can open bright perspectives for novel biomarkers and therapeutic discoveries. We propose that neuroimmune factors, for example, genetic, early-life trauma, infections, autoimmune diseases, and gut microbiota abnormalities, interact within each patient's life trajectory to determine the emergence of altered microglial states that we named bipolar disorder (BD)-associated microglial states. We hypothesize that these microglial states pair the systemic immune-inflammatory alterations present in patients with BD according to each disease phase (acute states vs. euthymia, early- vs. late-stage) and are characterized by critical changes in structure and functions that are progressive along the disease timeline and marked by a loss in homeostatic functions, culminating into final dystrophic states similar to those observed in neurodegenerative conditions.image