GBP5-triggered AIM2 inflammasome drives host defense and exacerbates disease severity duringinfection
Source: PubMed Central Open Access, NCBI / U.S. National Library of Medicine
is a major cause of abortion in cattle worldwide, leading to substantial economic losses in the livestock industry. As no effective drug or vaccine is currently available, a deeper understanding of the host immune response againstis essential for developing effective control strategies. The absent in melanoma 2 (AIM2) inflammasome is involved in host defense and regulation of disease pathology, while its role ininfection remains unclear. This study shows thatactivates the AIM2 inflammasome in wild-type (WT) murine peritoneal macrophage (PMϕs), characterized by increased expression of AIM2, pro-IL-1β, caspase-1 p20, and IL-1β p17, along with elevated IL-1β secretion and cell death rates. Guanylate-binding proteins (GBPs) are involved in regulating AIM2 inflammasome activation. Here, we observed that both GBP2 and GBP5 were upregulated by, but only GBP5 overexpression played a functional role, as its overexpression enhanced, whereas its knockdown significantly attenuated AIM2 inflammasome in WT PMϕs, suggestingactivates the AIM2 inflammasome in a GBP5-dependent manner. To further investigate the role of AIM2 in parasite infection,mice were used. InPMϕs, inflammasome activation was reduced, accompanied by increased parasite proliferation. In vivo,-infectedmice exhibited higher parasite loads but showed increased survival rates, reduced macrophage recruitment, decreased levels of IFN-γ, and IL-18, and alleviated pathological damage. In summary, our findings demonstrate that the A
Abstract
is a major cause of abortion in cattle worldwide, leading to substantial economic losses in the livestock industry. As no effective drug or vaccine is currently available, a deeper understanding of the host immune response againstis essential for developing effective control strategies. The absent in melanoma 2 (AIM2) inflammasome is involved in host defense and regulation of disease pathology, while its role ininfection remains unclear. This study shows thatactivates the AIM2 inflammasome in wild-type (WT) murine peritoneal macrophage (PMϕs), characterized by increased expression of AIM2, pro-IL-1β, caspase-1 p20, and IL-1β p17, along with elevated IL-1β secretion and cell death rates. Guanylate-binding proteins (GBPs) are involved in regulating AIM2 inflammasome activation. Here, we observed that both GBP2 and GBP5 were upregulated by, but only GBP5 overexpression played a functional role, as its overexpression enhanced, whereas its knockdown significantly attenuated AIM2 inflammasome in WT PMϕs, suggestingactivates the AIM2 inflammasome in a GBP5-dependent manner. To further investigate the role of AIM2 in parasite infection,mice were used. InPMϕs, inflammasome activation was reduced, accompanied by increased parasite proliferation. In vivo,-infectedmice exhibited higher parasite loads but showed increased survival rates, reduced macrophage recruitment, decreased levels of IFN-γ, and IL-18, and alleviated pathological damage. In summary, our findings demonstrate that the AIM2 inflammasome is activated byin a GBP5-dependent manner and plays a dual role by restricting parasite proliferation while exacerbating disease pathology. Supplementary Information The online version contains supplementary material available at 10.1186/s13567-026-01769-z. Abs1