Targeting Myeloid-Specific Integrin α9β1 Improves Short- and Long-Term Stroke Outcomes in Murine Models With Preexisting Comorbidities by Limiting Thrombosis and Inflammation

1区 · 医学

Article

作者: Jain, Manish ; Chorawala, Mehul ; Ghatge, Madankumar ; Dhanesha, Nirav ; Tripathi, Amit K. ; Lentz, Steven R. ; Doddapattar, Prakash ; Chauhan, Anil K. ; Kon, Shigeyuki ; Nayak, Manasa K. ; Bathla, Girish

Rationale:Currently, there is no effective intervention available that can reduce brain damage following reperfusion. Clinical studies suggest a positive correlation between the increased influx of neutrophils and severity of brain injury following reperfusion. Integrin α9β1 is highly expressed on activated neutrophils and contributes to stable adhesion, but its role in stroke outcome has not been demonstrated to date.Objective:We sought to determine the mechanistic role of myeloid-specific α9β1 in the progression of ischemic stroke in murine models with preexisting comorbidities.Methods and Results: We generated novel myeloid-specific α9-deficient ( α9−/− ) wild type ( α9fl/flLysMCre+/− ), hyperlipidemic ( α9fl/flLysMCre+/−Apoe−/− ), and aged (bone marrow chimeric) mice to evaluate stroke outcome. Susceptibility to ischemia/reperfusion injury was evaluated at 1, 7, and 28 days following reperfusion in 2 models of experimental stroke: filament and embolic. We found that peripheral neutrophils displayed elevated α9 expression following stroke. Irrespective of sex, genetic deletion of α9 in myeloid cells improved short- and long-term stroke outcomes in the wild type, hyperlipidemic, and aged mice. Improved stroke outcome and enhanced survival in myeloid-specific α9−/− mice was because of marked decrease in cerebral thromboinflammatory response as evidenced by reduced fibrin, platelet thrombi, neutrophil, NETosis, and decreased phospho-NF-κB (nuclear factor-κB), TNF (tumor necrosis factor)-α, and IL (interleukin)-1β levels. α9−/− mice were less susceptible to FeCl 3 injury-induced carotid artery thrombosis that was concomitant with improved regional cerebral blood flow following stroke as revealed by laser speckle imaging. Mechanistically, fibronectin containing extra domain A, a ligand for integrin α9, partially contributed to α9-mediated stroke exacerbation. Infusion of a specific anti-integrin α9 inhibitor into hyperlipidemic mice following reperfusion significantly reduced infarct volume and improved short- and long-term functional outcomes up to 28 days. Conclusions:We provide genetic and pharmacological evidence for the first time that targeting myeloid-specific integrin α9β1 improves short- and long-term functional outcomes in stroke models with preexisting comorbidities by limiting cerebral thrombosis and inflammation.

2020-03-12·Blood1区 · 医学

Targeting myeloid-cell specific integrin α9β1 inhibits arterial thrombosis in mice

1区 · 医学

Article

作者: Flora, Gagan D. ; Jain, Manish ; Nayak, Manasa K. ; Kon, Shigeyuki ; Chauhan, Anil K. ; Dhanesha, Nirav ; Doddapattar, Prakash

AbstractEvidence suggests that neutrophils contribute to thrombosis via several mechanisms, including neutrophil extracellular traps (NETs) formation. Integrin α9β1 is highly expressed on neutrophils when compared with monocytes. It undergoes affinity upregulation on neutrophil activation, and stabilizes adhesion to the activated endothelium. The role of integrin α9 in arterial thrombosis remains unexplored. We generated novel myeloid cell-specific integrin α9−/− mice (α9fl/flLysMCre+) to study the role of integrin α9 in arterial thrombosis. α9fl/fl littermates were used as controls. We report that α9fl/flLysMCre+ mice were less susceptible to arterial thrombosis in ferric chloride (FeCl3) and laser injury-induced thrombosis models with unaltered hemostasis. Neutrophil elastase-positive cells were significantly reduced in α9fl/flLysMCre+ mice concomitant with reduction in neutrophil count, myeloperoxidase levels, and red blood cells in the FeCl3 injury-induced carotid thrombus. The percentage of cells releasing NETs was significantly reduced in α9fl/flLysMCre+ mouse neutrophils stimulated with thrombin-activated platelets. Furthermore, we found a significant decrease in neutrophil-mediated platelet aggregation and cathepsin-G secretion in α9fl/flLysMCre+ mice. Transfusion of α9fl/fl neutrophils in α9fl/flLysMCre+ mice restored thrombosis similar to α9fl/fl mice. Treatment of wild-type mice with anti-integrin α9 antibody inhibited arterial thrombosis. This study identifies the potential role of integrin α9 in modulating arterial thrombosis.

2009-06-15·The Journal of Immunology2区 · 医学

α9 Integrin and Its Ligands Constitute Critical Joint Microenvironments for Development of Autoimmune Arthritis

2区 · 医学

Article

作者: Uede, Toshimitsu ; Minami, Akio ; Asano, Tsuyoshi ; Nakayama, Yosuke ; Kon, Shigeyuki ; Harada, Tanenobu ; Suzuki, Koji ; Li, Hong Mei ; Uehara, Jun ; Kurotaki, Daisuke ; Iwasaki, Norimasa ; Morimoto, Junko ; Kanayama, Masashi ; Miyazaki, Tadaaki ; Matsui, Yutaka ; Saito, Yoshinari ; Ito, Koyu ; Kimura, Chiemi

AbstractOsteopontin is critically involved in rheumatoid arthritis; however, the molecular cross-talk between osteopontin and joint cell components that leads to the inflammatory joint destruction is largely unknown. We found that not only osteopontin but also tenascin-C and their common receptor, α9 integrin, are expressed at arthritic joints. The local production of osteopontin and tenascin-C is mainly due to synovial fibroblasts and, to a lesser extent, synovial macrophages. Synovial fibroblasts and macrophages express α9 integrin, and autocrine and paracrine interactions of α9 integrin on synovial fibroblasts and macrophages and its ligands contribute differently to the production of proinflammatory cytokines and chemokines. α9 integrin is also involved in the recruitment and accumulation of inflammatory cells. Inhibition of α9 integrin function with an anti-α9 integrin Ab significantly reduces the production of arthrogenic cytokines and chemokines and ameliorates ongoing arthritis. Thus, we identified α9 integrin as a critical intrinsic regulator that controls the development of autoimmune arthritis.

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2024-10-24

·Pharmaceutical Technology

Alpha-9 becomes latest radiopharma to secure funds with $175m Series C

Alpha-9 Oncology has raised $175m in a Series C funding round to advance its pipeline of radiopharmaceuticals. Credit: eamesBot via Shutterstock. Alpha-9 Oncology is the latest radiopharma to raise funds, drawing in $175m in Series C financing, to advance its radiopharmaceutical candidates through clinical trials and expand its research and development (R&D) capabilities. Vancouver, Canada-based Alpha-9 shared that it will advance its pipeline of preclinical candidates to the “clinic-ready” stage. While the company has not disclosed which of its assets in particular will be advanced, the company has several preclinical programs targeting MC1R, PSMA, GRPR, CXCR4, and B1R, as per GlobalData’s Pharma Intelligence Center. In May 2024, Alpha-9 announced the dosing of the first patient in its Phase I study for the MC1R programme, dubbed A9-3202. This peptide-based radiopharmaceutical targets the melanocortin 1 receptor for imaging locally advanced or metastatic melanoma. The trial is evaluating A9-3202’s tumour uptake and distribution in normal tissue among participants with melanoma. This latest financing comes after a flood of investment into the radiopharma arena over the last few years. Earlier this month, Aktis Oncology raised $175m to support the development of its new radiopharmaceuticals, including a first-in-class Nectin-4-targeted miniprotein radioconjugate. Big pharma has jumped on the radiopharma train too, with Bristol Myers Squibb (BMS), Novartis , and Eli Lilly signing acquisition deals worth $4.2bn , $1.75bn , and $1.4bn, respectively. Alpha-9’s Series C – co-led by Lightspeed Venture Partners and Ascenta Capital – builds on a $75m Series B in December 2022, and a $8.9m Series A in 2021, three years after the company spun-out from the University of British Columbia. Other participating investors in this round included a16z Bio + Health, RA Capital Management, Janus Henderson Investors and Samsara BioCapital. See Also: UPFs fuelling ‘alarming rise of chronic diseases’ in india FDA grants ODD to Modalis’ MDL-101 to treat LAMA2-CMD Alpha-9 said its funding will also support ongoing investments in its discovery capabilities, as well as the expansion of manufacturing and isotope supply partnerships. The company recently completed the construction of a manufacturing facility in Vancouver, Canada. Last month, Telix Pharmaceuticals paid $230m upfront to acquire US-based radioisotope manufacturer RLS Radiopharmacies to expand its manufacturing footprint in the US. Venture financing for innovative radiopharmaceutical drugs has witnessed an approximately 550% increase from $63m in 2017 to $408m in 2023 YTD (year-to-date) total deal value in the US, according to GlobalData’s Pharma Intelligence Center Deals Database. GlobalData is the parent company of Pharmaceutical Technology. In the announcement accompanying the financing, Alpha-9’s CEO David Hirsch said: “Over the last few years, Alpha-9 has built a leading radiopharmaceutical company with a deep pipeline and robust infrastructure.”