Circulating hs-CRP as Disease-Modifying Target via Astrocytic Complement C3 Cas…

Elevated circulating high-sensitivity C-reactive protein (hs-CRP) functions as a disease-modifying factor through complement-mediated astrocytic activation rather than microglial IL-1β amplification. In this alternative mechanism, circulating hs-CRP binds to complement factor H (CFH) and disrupts complement regulation, leading to excessive C3 convertase activity and local C3a/C5a production within the central nervous system. Astrocytes, which express high levels of complement receptors C3aR and C5aR, become hyperactivated upon exposure to these complement fragments. This astrocytic activation triggers a distinct inflammatory cascade involving upregulation of complement component C3 synthesis and secretion, creating a positive feedback loop that amplifies complement-mediated neuroinflammation. The activated astrocytes also release complement factor B and properdin, further enhancing alternative complement pathway activity. This complement-centric mechanism differs from the traditional IL-1β/TLR4 pathway by operating through the C3/C5 convertase system and primarily targeting astrocytes rather than microglia. The resulting neuroinflammatory environment is characterized by complement deposition, astrogliosis, and compromised blood-brain barrier integrity. Therapeutic interventions targeting this pathway would focus on complement inhibitors (such as C3 or C5 antagonists) or astrocyte-specific complement receptor modulators rather than IL-1β or TLR4 inhibition. This mechanism suggests that hs-CRP serves as an upstream regulator of complement homeostasis, and its elevation in systemic inflammation directly translates to CNS pathology through complement-mediated astrocytic dysfunction. The pathway offers novel therapeutic targets for neuroinflammatory conditions where elevated hs-CRP correlates with disease progression, providing an alternative to cytokine-focused interventions.