Neuroimmune crosstalk in chronic neuroinflammation: microglial interactions and immune modulation

Abstract

Neuroinflammation is a fundamental feature of many chronic neurodegenerative diseases, where it contributes to disease onset, progression, and severity. This persistent inflammatory state arises from the activation of innate and adaptive immune responses within the central nervous system (CNS), orchestrated by a complex interplay of resident immune cells, infiltrating peripheral immune cells, and an array of molecular mediators such as cytokines, chemokines, and extracellular vesicles. Among CNS-resident cells, microglia play a central role, exhibiting a dynamic spectrum of phenotypes ranging from neuroprotective to neurotoxic. In chronic neurodegenerative diseases, sustained microglial activation often leads to the amplification of inflammatory cascades, reinforcing a pathogenic cycle of immune-mediated damage. Intercellular communication within the inflamed CNS is central to the persistence and progression of neuroinflammation. Microglia engage in extensive crosstalk with astrocytes, neurons, oligodendrocytes, and infiltrating immune cells, shaping both local and systemic inflammatory responses. These interactions influence key processes such as synaptic pruning, phagocytosis, blood-brain barrier integrity, and cytokine-mediated signaling. Understanding the mechanisms of cell-cell signaling in this context is critical for identifying therapeutic strategies to modulate the immune response and restore homeostasis. This review explores the key players in CNS neuroinflammation, with a focus on the role of microglia, the molecular pathways underlying intercellular communication, and potential therapeutic approaches to mitigate neuroinflammatory damage in chronic neurodegenerative diseases.

Keywords: astrocytes; cytokines; immune cells; microglia; neurodegenerative diseases; neuroimmune crosstalk; neuroinflammation; neurons.

Figure 1

Cellular and molecular mediators of neuroinflammation. The left panel (blue background) illustrates cells and signaling molecules in the homeostatic state, where the blood–brain barrier remains intact, regulating immune interactions and maintaining CNS balance. The right panel (red background) depicts neuroinflammation, characterized by activated microglia, reactive astrocytes, BBB disruption, infiltrating immune cells, and increased pro-inflammatory mediators. MG, microglia; AC, astrocyte; NTF, neurotrophic factors; D, debris; TGF, transforming growth factor; IL, interleukin; OD, oligodendrocyte; N, neuron; Treg, regulatory T cell; aSPM, anti-inflammatory specialized pro-resolving mediators; aCh, anti-inflammatory chemokines; aMG, activated microglia; aAC, activated astrocyte; TNF, tumor necrosis factor; pIC, peripheral immune cells; dN, degenerating neuron; proIC, pro-inflammatory cytokines; pCh, pro-inflammatory chemokines; pSPM, pro-inflammatory SPM; Mf-1, macrophage type 1; BBB, blood–brain-barrier; cBBB, compromised blood–brain-barrier.

Figure 2

Therapeutic modulation of neuroinflammation. Therapeutic strategies aimed at regulating microglial activity and immune responses hold potential for restoring homeostatic balance in the CNS. Approaches such as microglial reprogramming by targeting microglia activation, inhibition of pro-inflammatory cytokines and chemokines, and advanced treatments—including nanoparticle-based drug delivery, gene therapy, and cell-based interventions—may offer innovative avenues for modulating neuroinflammation and restoring homeostasis. aMG, activated microglia; dN, degenerating neuron; aAC, activated astrocyte; proIC, pro-inflammatory cytokines; pCh, pro-inflammatory chemokines; Mf-1, macrophage type 1; pIC, peripheral immune cell; aIC, anti-inflammatory cytokines; aCh, anti-inflammatory chemokines; AC, astrocyte; MG, microglia; NTF, neurotrophic factors; N, neuron.