Deficiency of Caspase-1 Attenuates HIV-1-Associated Atherogenesis in Mice

• Published in: International journal of molecular sciences 2023-08, Vol.24 (16), p.12871
• Main Authors: Alam, Mohammad Afaque, Caocci, Maurizio, Ren, Mi, Chen, Zheng, Liu, Fengming, Khatun, Mst Shamima, Kolls, Jay K, Qin, Xuebin, Burdo, Tricia H
• Format: Article
• Language: English
• Subjects: Analysis; animal models; Animals; Antiviral agents; Apolipoproteins E - genetics; Atherosclerosis; Atherosclerosis - genetics; Bone marrow; Caspase 1 - genetics; caspase-1; Cholesterol; Coronary vessels; Cytokines; Genes; Health aspects; HIV; HIV (Viruses); HIV infection; HIV Infections - complications; HIV Infections - genetics; HIV-1; Human immunodeficiency virus; Inflammation; macrophage; Macrophages; Mice; Plaque, Atherosclerotic - genetics; Spleen; Triglycerides
• ISSN: 1422-0067; 1661-6596; 1422-0067
• DOI: 10.3390/ijms241612871

Within arterial plaque, HIV infection creates a state of inflammation and immune activation, triggering NLRP3/caspase-1 inflammasome, tissue damage, and monocyte/macrophage infiltration. Previously, we documented that caspase-1 activation in myeloid cells was linked with HIV-associated atherosclerosis in mice and people with HIV. Here, we mechanistically examined the direct effect of caspase-1 on HIV-associated atherosclerosis. Caspase-1-deficient ( ) mice were crossed with HIV-1 transgenic (Tg26 ) mice with an atherogenic -deficient ( ) background to create global caspase-1-deficient mice ( . Caspase-1-sufficient ( ) mice served as the controls. Next, we created chimeric hematopoietic cell-deficient mice by reconstituting irradiated mice with bone marrow cells transplanted from (BMT ) or (BMT ) mice. Global caspase-1 knockout in mice suppressed plaque deposition in the thoracic aorta, serum IL-18 levels, and ex vivo foam cell formation. The deficiency of caspase-1 in hematopoietic cells resulted in reduced atherosclerotic plaque burden in the whole aorta and aortic root, which was associated with reduced macrophage infiltration. Transcriptomic analyses of peripheral mononuclear cells and splenocytes indicated that caspase-1 deficiency inhibited caspase-1 pathway-related genes. These results document the critical atherogenic role of caspase-1 in chronic HIV infection and highlight the implication of this pathway and peripheral immune activation in HIV-associated atherosclerosis.