tetano
Editor, Senior Moderator
Neurochem Int
. 2026 Feb 2:106122.
doi: 10.1016/j.neuint.2026.106122. Online ahead of print.
ERK-Dependent Astrocytic PAI-1 Induction by Influenza A Virus Disrupts the Neurochemical Balance of the PAI-1/tPA Axis
Eun-Sook Park[SUP] 1 [/SUP], Bo-Bae Park[SUP] 2 [/SUP], Ryeong-Eun Kim[SUP] 3 [/SUP], Yoonseo Hong[SUP] 3 [/SUP], Kyoung Ja Kwon[SUP] 3 [/SUP], Chan Young Shin[SUP] 4 [/SUP]
Affiliations
Background: Influenza A virus (IAV), although primarily a respiratory pathogen, is increasingly recognized to affect central nervous system (CNS) function. Astrocytes are key regulators of neurochemical homeostasis and neuroinflammation, but the molecular pathways underlying their response to IAV remain incompletely defined.
Methods: Primary rat astrocytes were infected with wild-type IAV (PR8, H1N1) or PB1-F2-deficient IAV (PB1-F2[-]). Regulation of the plasminogen activator inhibitor-1 (PAI-1)/tissue-type plasminogen activator (tPA) system was examined by qPCR, Western blotting, zymography, and ELISA. ERK pathway activation was assessed using phospho-specific antibodies, and pathway dependency was tested using the ERK inhibitor U0126. Functional consequences on neurons were evaluated by neurite outgrowth assays using astrocyte-conditioned medium (ACM).
Results: IAV infection induced a robust increase in astrocytic PAI-1 expression and a marked reduction in tPA activity, accompanied by selective activation of ERK signaling. Pharmacological ERK inhibition completely abolished PAI-1 upregulation, indicating that ERK is required for this neurochemical shift. PB1-F2 deletion did not alter PAI-1 induction but partially modified cytokine expression profiles, demonstrating PB1-F2-independent regulation of the PAI-1/tPA axis. Compared with lipopolysaccharide (LPS), IAV elicited substantially lower cytokine levels yet induced markedly higher PAI-1 expression, suggesting a sustained antifibrinolytic phenotype. Neurons exposed to ACM from IAV-infected astrocytes exhibited reduced neurite extension and branching, indicating impaired neuronal structural development through paracrine mechanisms.
Conclusions: IAV triggers an ERK-dependent induction of PAI-1 in astrocytes, leading to suppression of tPA activity and disruption of neuronal outgrowth. These findings identify a neurochemical mechanism linking astrocyte-specific MAPK signaling to neuroinflammatory and antifibrinolytic dysfunction during viral infection.
Keywords: Astrocyte; ERK signaling; Influenza A virus; Neuroinflammation; Neuronal outgrowth; PAI-1/tPA axis.
. 2026 Feb 2:106122.
doi: 10.1016/j.neuint.2026.106122. Online ahead of print.
ERK-Dependent Astrocytic PAI-1 Induction by Influenza A Virus Disrupts the Neurochemical Balance of the PAI-1/tPA Axis
Eun-Sook Park[SUP] 1 [/SUP], Bo-Bae Park[SUP] 2 [/SUP], Ryeong-Eun Kim[SUP] 3 [/SUP], Yoonseo Hong[SUP] 3 [/SUP], Kyoung Ja Kwon[SUP] 3 [/SUP], Chan Young Shin[SUP] 4 [/SUP]
Affiliations
- PMID: 41638582
- DOI: 10.1016/j.neuint.2026.106122
Background: Influenza A virus (IAV), although primarily a respiratory pathogen, is increasingly recognized to affect central nervous system (CNS) function. Astrocytes are key regulators of neurochemical homeostasis and neuroinflammation, but the molecular pathways underlying their response to IAV remain incompletely defined.
Methods: Primary rat astrocytes were infected with wild-type IAV (PR8, H1N1) or PB1-F2-deficient IAV (PB1-F2[-]). Regulation of the plasminogen activator inhibitor-1 (PAI-1)/tissue-type plasminogen activator (tPA) system was examined by qPCR, Western blotting, zymography, and ELISA. ERK pathway activation was assessed using phospho-specific antibodies, and pathway dependency was tested using the ERK inhibitor U0126. Functional consequences on neurons were evaluated by neurite outgrowth assays using astrocyte-conditioned medium (ACM).
Results: IAV infection induced a robust increase in astrocytic PAI-1 expression and a marked reduction in tPA activity, accompanied by selective activation of ERK signaling. Pharmacological ERK inhibition completely abolished PAI-1 upregulation, indicating that ERK is required for this neurochemical shift. PB1-F2 deletion did not alter PAI-1 induction but partially modified cytokine expression profiles, demonstrating PB1-F2-independent regulation of the PAI-1/tPA axis. Compared with lipopolysaccharide (LPS), IAV elicited substantially lower cytokine levels yet induced markedly higher PAI-1 expression, suggesting a sustained antifibrinolytic phenotype. Neurons exposed to ACM from IAV-infected astrocytes exhibited reduced neurite extension and branching, indicating impaired neuronal structural development through paracrine mechanisms.
Conclusions: IAV triggers an ERK-dependent induction of PAI-1 in astrocytes, leading to suppression of tPA activity and disruption of neuronal outgrowth. These findings identify a neurochemical mechanism linking astrocyte-specific MAPK signaling to neuroinflammatory and antifibrinolytic dysfunction during viral infection.
Keywords: Astrocyte; ERK signaling; Influenza A virus; Neuroinflammation; Neuronal outgrowth; PAI-1/tPA axis.