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

Mohammad Afaque Alam; Maurizio Caocci; Mi Ren; Zheng Chen; Fengming Liu; Mst Shamima Khatun; Jay K Kolls; Xuebin Qin; Tricia H Burdo

doi:10.3390/ijms241612871

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

Int J Mol Sci. 2023 Aug 17;24(16):12871. doi: 10.3390/ijms241612871.

Authors

Mohammad Afaque Alam^{1

2}, Maurizio Caocci³, Mi Ren^{1

2}, Zheng Chen^{1

2}, Fengming Liu^{1

2}, Mst Shamima Khatun⁴, Jay K Kolls^{4

5}, Xuebin Qin^{1

2}, Tricia H Burdo³

Affiliations

¹ Department of Comparative Pathology, Tulane National Primate Research Center, Tulane University School of Medicine, Tulane University, 18703 Three Rivers Road, Covington, LA 70433, USA.
² Department of Microbiology and Immunology, School of Medicine, Tulane University, New Orleans, LA 70112, USA.
³ Department of Microbiology, Immunology and Inflammation, Center for NeuroVirology and Gene Editing, Lewis Katz School of Medicine, Temple University, Philadelphia, PA 19140, USA.
⁴ Departments of Pediatrics & Medicine, Center for Translational Research in Infection and Inflammation, Tulane University School of Medicine, New Orleans, LA 70112, USA.
⁵ Department of Medicine, Section of Pulmonary Diseases, Critical Care and Environmental Medicine, Tulane University School of Medicine, New Orleans, LA 70112, USA.

Abstract

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.

Keywords: HIV-1; animal models; atherosclerosis; caspase-1; macrophage.

MeSH terms

Animals
Apolipoproteins E / genetics
Atherosclerosis* / genetics
Caspase 1 / genetics
HIV Infections* / complications
HIV Infections* / genetics
HIV-1*
Mice
Plaque, Atherosclerotic* / genetics

Substances

Apolipoproteins E
Caspase 1
Casp1 protein, mouse

Abstract

MeSH terms

Substances

Grants and funding