Pericytes are specialized cells located in close proximity to endothelial cells within the microvasculature. They play a crucial role in regulating blood flow, stabilizing vessel walls, and maintaining the integrity of the blood–brain barrier. The loss of pericytes has been associated with the development and progression of various diseases, such as diabetes, Alzheimer’s disease, sepsis, stroke, and traumatic brain injury. This review examines the detection of pericyte loss in different diseases, explores the methods employed to assess pericyte coverage, and elucidates the potential mechanisms contributing to pericyte loss in these pathological conditions. Additionally, current therapeutic strategies targeting pericytes are discussed, along with potential future interventions aimed at preserving pericyte function and promoting disease mitigation.

Introduction: Kallistatin levels in the circulation are reduced in patients with sepsis and liver disease. Transgenic mice expressing kallistatin are resistant to lipopolysaccharide (LPS)-induced mortality. Here, we investigated the effect of kallistatin on survival and organ damage in mouse models of established sepsis. Methods: Mice were rendered septic by cecal ligation and puncture (CLP), or endotoxemic by LPS injection. Recombinant human kallistatin was administered intravenously six hours after CLP, or intraperitoneally four hours after LPS challenge. The effect of kallistatin treatment on organ damage was examined one day after sepsis initiation, and mouse survival was monitored for four to six days. Results: Human kallistatin was detected in mouse serum of kallistatin-treated mice. Kallistatin significantly reduced CLP-induced renal injury as well as blood urea nitrogen, serum creatinine, interleukin-6 (IL-6), and high mobility group box-1 (HMGB1) levels. In the lung, kallistatin decreased malondialdehyde levels and HMGB1 and toll-like receptor-4 (TLR4) synthesis, but increased suppressor of cytokine signaling-3 (SOCS3) expression. Moreover, kallistatin attenuated liver injury, serum alanine transaminase (ALT) levels and hepatic tumor necrosis factor-α (TNF-α) synthesis. Furthermore, delayed kallistatin administration improved survival in CLP mice by 38%, and LPS-treated mice by 42%. In LPS-induced endotoxemic mice, kallistatin attenuated kidney damage in association with reduced serum creatinine, IL-6 and HMGB1 levels, and increased renal SOCS3 expression. Kallistatin also decreased liver injury in conjunction with diminished serum ALT levels and hepatic TNF-α and TLR4 expression. In cultured macrophages, kallistatin through its active site increased SOCS3 expression, but this effect was blocked by inhibitors of tyrosine kinase, protein kinase C and extracellular signal-regulated kinase (ERK), indicating that kallistatin stimulates a tyrosine-kinase-protein kinase C-ERK signaling pathway. Conclusions: This is the first study to demonstrate that delayed human kallistatin administration is effective in attenuating multi-organ injury, inflammation and mortality in mouse models of polymicrobial infection and endotoxemia. Thus, kallistatin therapy may provide a promising approach for the treatment of sepsis in humans.

Background: Alzheimer’s disease (AD) is associated with cognitive impairment and neuro‐inflammation. Dysregulated activation of microglia and astrocytes induces neuro‐inflammation, and reactive astrocytes have been classified into A1 neurotoxic and A2 neuroprotective phenotypes. A1 astrocytes are induced by activated neuro‐inflammatory microglia via secreting IL‐1α, TNFα and C1q, and contributing to inflammation and neuronal cell death. However, the processes that govern astrocyte transformation and their role in AD development remains unclear. Increased friend leukemia virus integration 1 (Fli‐1) levels were observed in the hippocampus of brain tissue from AD patients and 5xFAD mice, a murine model of AD. While inhibition of Fli‐1 reduced pericyte loss, Aβ deposition and BBB dysfunction in the 5xFAD mice. However, Fli‐1’s specific role in astrocyte activation in AD remains unexplored.Method: Fli‐1 levels and A1 phenotype astrocyte number were detected in brain tissues from WT mice, 5xFAD mice and inducible Fli‐1 KO 5xFAD mice. Control or Fli‐1 antisense oligonucleotide Gapmers were injected into the hippocampus of 5xFAD mice at 3 and 4.5 months of age. A1 phenotype astrocyte number, inflammatory mediators and cognitive deficits were evaluated at 6 months of age. Cultured mouse astrocytes were transfected with control or Fli‐1 Gapmers for 24 h and followed stimulation with IL‐1α, TNFα and C1q for another 24 h. The expression levels of Fli‐1 and inflammatory mediators, and A1 phenotype astrocyte number were determined.Result: Fli‐1 levels are higher in the astrocytes in hippocampus of 5xFAD mice, and corresponded with increased astrocyte activation, A1 astrocyte number, inflammation and cognitive impairment. While 5xFAD mice with inducible Fli‐1 KO exhibited decreased astrocyte activation, attenuated inflammation, and mitigated cognitive impairment. Knockdown of Fli‐1 in cultured mouse astrocytes with Fli‐1 Gapmers suppressed activated microglia‐induced astrocyte activation, and inhibited IL‐1α, TNFα and C1q‐indcued A1 astrocyte transformation in vitro. Moreover, injection of Fli‐1 Gapmers into the hippocampus of 5xFAD mice significantly decreased Fli‐1 levels and reduced A1 astrocyte number.Conclusion: The elevated Fli‐1 levels contribute to astrocyte dysfunction and A1 astrocyte transformation in AD. Targeting Fli‐1 could be a therapeutic approach to prevent or mitigate AD‐induced astrocyte dysfunction and cognitive impairment, offering potential clinical applications.

Fli-1, a member of the ETS transcription factor family, has been implicated in multiple inflammatory and immune-related disorders, including sepsis, lupus, Alzheimer's disease, and post-traumatic stress disorder (PTSD). Recent studies further suggest a critical role for Fli-1 in CD4⁺ T cells in graft-versus-host disease, systemic sclerosis, and PTSD; however, its precise function and regulation during inflammatory CD4⁺ T cell responses remain incompletely understood. Wild-type and CD4⁺ T cell-specific Fli-1 knockout mice were administered LPS via intraperitoneal injection. Survival rates and splenic T cell activation were subsequently assessed. In vitro, cultured Jurkat and HEK cells were utilized to investigate the STUB1/Fli-1-related signaling pathway. Here, we demonstrate that Fli-1 expression is markedly upregulated in splenic CD4⁺ T cells in a murine model of endotoxemia. CD4⁺ T cell-specific deletion of Fli-1 significantly improves survival and attenuates splenic CD4⁺ T cell activation. Mechanistically, we identify STUB1 as a novel E3 ubiquitin ligase for Fli-1 that promotes K27-linked ubiquitination and proteasomal degradation under basal conditions. Inflammatory stimulation disrupts the STUB1/HSP70 interaction, reducing STUB1-mediated ubiquitination and enhancing Fli-1 protein stability. Consistent with these findings, Fli-1 knockout reduces TNFα, IFNγ, and IL-10 expression, whereas STUB1 knockout enhances their expression in Jurkat cells. Gain- and loss-of-function studies further reveal that Fli-1 modulates NFκB signaling, a key pathway in T cell activation. Collectively, our results identify the STUB1/Fli-1 axis as a previously unrecognized regulator of CD4⁺ T cell function and a potential therapeutic target for inflammatory diseases.

Local disruption of iron homeostasis leading to oxidative stress is considered one of the main mechanisms of asbestos-dependent cyto-/genotoxicity. Another aspect contributing to the risk of developing pathological consequences upon asbestos exposure is due to individual genetic fac-tors. In a previous study we identified a coding SNP in the hephaestin gene (HEPH) exerting a protective activity against the development of asbestos related thoracic cancers. Heph is a fer-roxidase which promotes iron export in concert with the permease ferroportin (Fpn1). Here, we performed an in-depth functional characterization of the HephD568H variant to gain insights on the molecular basis of its protective activity in asbestos-related carcinogenesis. We demonstrat-ed that HephD568H complexes with Fpn1 and possesses a full ferroxidase activity. Despite being more efficiently recruited at the plasma membrane, HephD568H is severely hampered in (iron-depleted) apo-Tfn binding, whose interaction with the WT ferroxidase emerged as a novel mechanism to perceive brain iron needs. Heph in human lung is expressed by pericytes and fi-broblasts and lung pericytes were shown to respond to iron request by up-regulating the iron exporter pair. These findings extend to the pulmonary vascular unit the paradigm of local iron regulation uncovered at the blood-brain barrier. Moreover, they mechanistically correlate alter-ations in iron sensing with the risk of developing asbestos-dependent malignancies.