Activation of the AIM2 Receptor in Circulating Cells of Post-COVID-19 Patients With Signs of Lung Fibrosis Is Associated With the Release of IL-1α, IFN-α and TGF-β

Abstract

Severe acute respiratory syndrome-coronavirus-2 (SARS‐CoV‐2), responsible for COVID-19, has caused a global pandemic. Observational studies revealed a condition, herein called as Long-COVID syndrome (PC), that affects both moderately and severely infected patients, reducing quality-of-life. The mechanism/s underlying the onset of fibrotic-like changes in PC are still not well defined. The goal of this study was to understand the involvement of the Absent in melanoma-2 (AIM2) inflammasome in PC-associated lung fibrosis-like changes revealed by chest CT scans. Peripheral blood mononuclear cells (PBMCs) obtained from PC patients who did not develop signs of lung fibrosis were not responsive to AIM2 activation by Poly dA:dT. In sharp contrast, PBMCs from PC patients with signs of lung fibrosis were highly responsive to AIM2 activation, which induced the release of IL-1α, IFN-α and TGF-β. The recognition of Poly dA:dT was not due to the activation of cyclic GMP-AMP (cGAMP) synthase, a stimulator of interferon response (cGAS-STING) pathways, implying a role for AIM2 in PC conditions. The release of IFN-α was caspase-1- and caspase-4-dependent when AIM2 was triggered. Instead, the release of pro-inflammatory IL-1α and pro-fibrogenic TGF-β were inflammasome independent because the inhibition of caspase-1 and caspase-4 did not alter the levels of the two cytokines. Moreover, the responsiveness of AIM2 correlated with higher expression of the receptor in circulating CD14+ cells in PBMCs from patients with signs of lung fibrosis.

Breaking Bad: Inflammasome Activation by Respiratory Viruses

“…Together, these studies provide clinical and mechanistic evidence that the NLRP3 inflammasome is suppressed at the early stages of SARS-CoV-2 infection and overactivated at later stages, and this could be the main cause of the cytokine storm seen in severe COVID-19 patients. The later hyperactivation of the inflammasome could also help explain its harmful involvement in the long-COVID syndrome, as it has been reported that monocytes from patients with long-COVID syndrome display increased AIM2 inflammasome expression and responsiveness, and this was associated with lung fibrosis and worse respiratory symptoms [82].…”

Inflammasomes during SARS-CoV-2 infection and development of their corresponding inhibitors

“…Indeed, considerable levels of AIM-2 were detected in monocytes infected by SARS-CoV-2 (Junqueira et al, 2021). Furthermore, AIM-2 receptor activation was observed in peripheral blood mononuclear cells (PBMCs) from post-Covid-19 patients that presented lung injuries (Colarusso et al, 2022). It was speculated that the ability of SARS-CoV-2 to induce AIM2 inflammasome response is due to the presence of cell free DNA (cfDNA) in several tissues of COVID-19 patient including lungs.…”

Association between COVID-19 Severity and Expression of Viral Nucleic Acid Sensor Genes in Peripheral Blood Mononuclear Cells and Nasopharyngeal Epithelial Cells

“…16 Colarusso et al showed that AIM2 could trigger inflammation and programmed cell death by processing interleukin IL-1, IL-18, and pro-caspase 1 and activating them. 33 Other research found a potent correlation between inflammasome-mediated inflammation and Gradermin D in severe COVID-19 cases as opposed to those with milder symptoms. They also proposed that this could be attributed to the high production of AIM2 and highlighted in the immunopathogenesis of COVID-19 patients.…”