The dual nature of neuroinflammation in networked brain

Abstract

Neuroinflammation is a dynamic, context-sensitive process that plays essential roles in brain development, maintenance, and response to injury. It reflects a finely balanced neuroimmune state-facilitating repair and adaptation under homeostatic conditions, while also contributing to dysfunction when dysregulated or chronically activated. In this mini-review, we examine the cellular and molecular mechanisms underlying neuroinflammatory responses, focusing on the roles of microglia and astrocytes, their bidirectional communication with neurons, and their interaction with peripheral immune signals. We describe how various stimuli-including aging, protein aggregates, and cellular stress-modulate glial function and shift immune activity toward protective or deleterious outcomes. Special attention is given to endogenous regulatory pathways, including cytokine signaling, receptor-mediated crosstalk, and immunometabolic cues that determine the resolution or persistence of inflammation. We further discuss shared and disease-specific features of neuroinflammation across neurological disorders, offering a systems-level perspective on how immune activity contributes to neural resilience or degeneration. This integrated view aims to inform future studies on neuroimmune dynamics in health and disease.

Keywords: CNS; astrocytes; brain; microglia; neuroimmune interactions; neuroinflammation; neurological disorders; neurons.

Figure 1

This simplified scheme illustrates dynamic cellular interactions in the brain across physiological and neuroinflammatory conditions. (A) Under homeostatic conditions, the CNS maintains balanced immune surveillance through tightly regulated BBB function and glial–neuronal crosstalk. Microglia, astrocytes, and oligodendrocyte-lineage cells support synaptic integrity, modulate neurotransmission, and contribute to developmental pruning and waste clearance. Anti-inflammatory cytokines, along with complement components, sustain a neuroprotective environment and prevent excessive immune activation. (B) Diverse initiators —including endogenous damage signals, exogenous pathogens, and genetic risk factors—can shift the brain from a homeostatic to a reactive immune state. These triggers affect glial phenotypes, BBB permeability, and neuroimmune signaling, potentially initiating a cascade toward chronic inflammation. (C) In pathological neuroinflammation, sustained activation of glial cells, infiltration of peripheral immune cells, and impaired neuronal feedback create a self-reinforcing loop of inflammatory signaling. Microglia can adopt disease-associated states such as DAM (disease-associated microglia) or LDAM (lipid-droplet-accumulating microglia), which initially aid clearance but may drive chronic inflammation and dysfunction. This dysregulation contributes to BBB disruption, synaptic impairment, and progressive neuronal damage, promoting the development of neurological and neurodegenerative disorders.BBB, blood-brain barrier; C1q, complement component; DAM, disease associated microglia; ROS, reactive oxygen species.

Figure 2

Mechanistic overview of neuroinflammation across major neurodegenerative diseases. This schematic illustrates the initiation and regulation of neuroinflammatory responses in AD, PD, and MS. The top panel highlights key genetic risk factors associated with each condition. The central section outlines shared and disease-specific inflammatory mechanisms, including innate immune responses to protein aggregates (AD, PD), autoimmune infiltration (MS), and chronic activation of microglia and astrocytes. These immune processes converge on a maladaptive inflammatory state that disrupts CNS homeostasis and promotes neuronal dysfunction. Despite their distinct etiologies, all three disorders involve persistent glial dysregulation, impaired resolution, and sustained neuroinflammation. The bottom panel depicts characteristic pathological outcomes associated with each disease. MG, microglia; AC, astrocyte; BBB, blood-brane-barrier; IL, interleukin; TNF, tumor necrosis factor; ROS, reactive oxygen species; pIC, peripheral immune cells; pC, peripheral cytokines; Mo, monocytes; aTC, autoreactive T cells; aBC, autoreactive B cells; aAb, auto-antibodies; Aβ, amyloid-β; dN, degenerating neuron; C3, complement component; LB, Lewis body; α-Sy, α-synuclein; dDN, degenerating dopaminergic neuron; pM, proinflammatory mediators; NLRP, inflammasome; dM, dysfunctional mitochondria; dmN, degenerating demyelinated neuron; Chemo, chemokines.