Extracellular matrix-derived matrikines as emerging modulators of neuroinflammation and central nervous system signaling

Abstract Neuroinflammation underlies many neurodegenerative disorders and is orchestrated by interactions between microglia, astrocytes, and neurons. While cytokines, chemokines, and damage-associated molecular patterns (DAMPs) are established neuroimmune mediators, extracellular matrix (ECM)-derived protein fragments, collectively termed matrikines, have received little attention in the central nervous system (CNS). Emerging evidence suggests that matrikines constitute a distinct and functionally important class of neuroimmune modulators. This review focuses on six CNS-relevant matrikines: type I collagen-derived acetylated Pro-Gly-Pro (Ac-PGP) and Gly-His-Lys (GHK); laminin-derived Ile-Lys-Val-Ala-Val (IKVAV) and Tyr-Ile-Gly-Ser-Arg (YIGSR); elastin-derived Val-Gly-Val-Ala-Pro-Gly (VGVAPG); and endorepellin, corresponding to domain V of perlecan. We describe their generation, receptor interactions, and signaling properties, and summarize their established effects in peripheral tissues and the limited evidence for CNS-specific roles. Current findings indicate that CNS matrikines may arise by peripheral entry through a compromised blood-brain barrier (BBB), proteolysis of the BBB basement membrane, or local degradation of CNS interstitial matrix and perineuronal nets during injury or disease. Their CNS effects are highly context- and cell-specific, ranging from neuroprotection and enhanced neuronal survival to modulation of microglial and astrocytic functions, cell migration, autophagy, and direct neurotoxicity. Collectively, evidence supports matrikines as CNS signaling molecules that complement classical immune mediators. Of note, studies using human CNS cells and tissues remain largely absent and should be prioritized to assess translational relevance. Systematic profiling of CNS matrikines, combined with mechanistic studies of their cell-specific signaling, especially in human cells, may reveal novel biomarkers and therapeutic targets, offering new avenues for intervention in neurodegenerative and other neurological disorders.