Roles of IL-34 in neurological diseases: neuroprotection, inflammatory regulation, and myeloid plasticity

Interleukin-34 (IL-34) is a brain-enriched cytokine and a tissue-restricted ligand of colony-stimulating factor-1 receptor (CSF-1R) that plays an important role in microglial development, survival, and functional specialization. A growing body of evidence indicates that IL-34 is dysregulated in both central and peripheral nervous system diseases and exerts pleiotropic effects not only through CSF-1R but also through non-canonical receptors, including TREM2, syndecan-1, and PTP-ζ. Under physiological conditions, IL-34 is constitutively produced predominantly by neurons across both the central and peripheral nervous systems. However, in pathological settings, its cellular sources expand dynamically: in CNS diseases, IL-34 is primarily derived from stressed neurons and reactive astrocytes, whereas in PNS disorders, it is robustly upregulated by injured sensory neurons, satellite glial cells, and reactive Schwann cells. IL-34 contributes to the regulation of resident glia in the CNS, while evidence from peripheral immune disorders suggests that it may also influence infiltrating myeloid-cell adaptation under pathological conditions. In this review, we highlight the multiple effects of IL-34 and its receptor network on CNS-resident, peripheral glial, and peripheral immune cells, with particular attention to the available data supporting its dual role in neuroprotection and inflammatory amplification. We synthesize recent findings regarding IL-34's role in myeloid reprogramming, particularly in orchestrating transcriptional and functional phenotypic shifts. While current literature provides evidence linking IL-34 to these transcriptional changes, its contribution to metabolic and epigenetic remodeling remains an emerging field. Furthermore, our findings summarized in this manuscript may help evaluate whether targeting IL-34-related pathways can be exploited for therapeutic intervention in neurodevelopmental, neurodegenerative, cerebrovascular, and peripheral nerve pathologies.