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

Autor: Mohammad Afaque Alam, Maurizio Caocci, Mi Ren, Zheng Chen, Fengming Liu, Mst Shamima Khatun, Jay K. Kolls, Xuebin Qin, Tricia H. Burdo
Jazyk: angličtina
Rok vydání: 2023
Předmět:
Zdroj: International Journal of Molecular Sciences, Vol 24, Iss 16, p 12871 (2023)
Druh dokumentu: article
ISSN: 1422-0067
1661-6596
DOI: 10.3390/ijms241612871
Popis: 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 (Casp-1−/−) mice were crossed with HIV-1 transgenic (Tg26+/−) mice with an atherogenic ApoE-deficient (ApoE−/−) background to create global caspase-1-deficient mice (Tg26+/−/ApoE−/−/Casp-1−/−). Caspase-1-sufficient (Tg26+/−/ApoE−/−/Casp-1+/+) mice served as the controls. Next, we created chimeric hematopoietic cell-deficient mice by reconstituting irradiated ApoE−/− mice with bone marrow cells transplanted from Tg26+/−/ApoE−/−/Casp-1−/− (BMT Casp-1−/−) or Tg26+/−/ApoE−/−/Casp-1+/+ (BMT Casp-1+/+) 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.
Databáze: Directory of Open Access Journals
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