TY - JOUR
T1 - Bystander monocytic cells drive infection-independent NLRP3 inflammasome response to SARS-CoV-2
AU - Hsieh, Leon L.
AU - Looney, Monika
AU - Figueroa, Alexis
AU - Massaccesi, Guido
AU - Stavrakis, Georgia
AU - Anaya, Eduardo U.
AU - D'Alessio, Franco R.
AU - Ordonez, Alvaro A.
AU - Pekosz, Andrew S.
AU - DeFilippis, Victor R.
AU - Karakousis, Petros C.
AU - Karaba, Andrew H.
AU - Cox, Andrea L.
N1 - Publisher Copyright:
© 2024 Hsieh et al.
PY - 2024/10
Y1 - 2024/10
N2 - The pathogenesis of COVID-19 is associated with a hyperinflammatoryimmune response. Monocytes and macrophages play a central role in this hyperinflammatoryresponse to SARS-CoV-2. NLRP3 inflammasomeactivation has been observed in monocytes of patients with COVID-19, but the mechanism and consequences of inflammasomeactivation require further investigation. In this study, we inoculated a macrophage-like THP-1 cell line, primary differentiatedhuman nasal epithelial cell (hNEC) cultures, and primary monocytes with SARS-CoV-2. We found that the activation of the NLRP3 inflammasomein macrophages does not rely on viral replication, receptor-mediated entry, or actin-dependent entry. SARS-CoV-2 productively infected hNEC cultures without triggering the production of inflammasomecytokines IL-18 and IL-1β. Importantly, these cytokines did not inhibit viral replication in hNEC cultures. SARS-CoV-2 inoculation of primary monocytes led to inflammasomeactivation and induced a macrophage phenotype in these cells. Monocytic cells from bronchoalveolar lavage (BAL) fluid,but not from peripheral blood, of patients with COVID-19, showed evidence of inflammasomeactivation, expressed the proinflammatorymarker CD11b, and displayed oxidative burst. These findingshighlight the central role of activated macrophages, as a result of direct viral sensing, in COVID-19 and support the inhibition of IL-1β and IL-18 as potential therapeutic strategies to reduce immunopathology without increasing viral replication. IMPORTANCE Inflammasomeactivation is associated with severe COVID-19. The impact of inflammasomeactivation on viral replication and mechanistic details of this activation are not clarified.This study advances our understanding of the role of inflammasomeactivation in macrophages by identifying TLR2, NLRP3, ASC, and caspase-1 as dependent factors in this activation. Further, it highlights that SARS-CoV-2 inflammasomeactivation is not a feature of nasal epithelial cells but rather activation of bystander macrophages in the airway. Finally, we demonstrate that two pro inflammatorycytokines produced by inflammasomeactivation, IL-18 and IL-1β, do not restrict viral replication and are potential targets to ameliorate pathological inflammationin severe COVID-19.
AB - The pathogenesis of COVID-19 is associated with a hyperinflammatoryimmune response. Monocytes and macrophages play a central role in this hyperinflammatoryresponse to SARS-CoV-2. NLRP3 inflammasomeactivation has been observed in monocytes of patients with COVID-19, but the mechanism and consequences of inflammasomeactivation require further investigation. In this study, we inoculated a macrophage-like THP-1 cell line, primary differentiatedhuman nasal epithelial cell (hNEC) cultures, and primary monocytes with SARS-CoV-2. We found that the activation of the NLRP3 inflammasomein macrophages does not rely on viral replication, receptor-mediated entry, or actin-dependent entry. SARS-CoV-2 productively infected hNEC cultures without triggering the production of inflammasomecytokines IL-18 and IL-1β. Importantly, these cytokines did not inhibit viral replication in hNEC cultures. SARS-CoV-2 inoculation of primary monocytes led to inflammasomeactivation and induced a macrophage phenotype in these cells. Monocytic cells from bronchoalveolar lavage (BAL) fluid,but not from peripheral blood, of patients with COVID-19, showed evidence of inflammasomeactivation, expressed the proinflammatorymarker CD11b, and displayed oxidative burst. These findingshighlight the central role of activated macrophages, as a result of direct viral sensing, in COVID-19 and support the inhibition of IL-1β and IL-18 as potential therapeutic strategies to reduce immunopathology without increasing viral replication. IMPORTANCE Inflammasomeactivation is associated with severe COVID-19. The impact of inflammasomeactivation on viral replication and mechanistic details of this activation are not clarified.This study advances our understanding of the role of inflammasomeactivation in macrophages by identifying TLR2, NLRP3, ASC, and caspase-1 as dependent factors in this activation. Further, it highlights that SARS-CoV-2 inflammasomeactivation is not a feature of nasal epithelial cells but rather activation of bystander macrophages in the airway. Finally, we demonstrate that two pro inflammatorycytokines produced by inflammasomeactivation, IL-18 and IL-1β, do not restrict viral replication and are potential targets to ameliorate pathological inflammationin severe COVID-19.
KW - Inflammasome
KW - NLRP3
KW - SARS-CoV-2
KW - cytokines
KW - macrophages
UR - http://www.scopus.com/inward/record.url?scp=85206958785&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85206958785&partnerID=8YFLogxK
U2 - 10.1128/mbio.00810-24
DO - 10.1128/mbio.00810-24
M3 - Article
C2 - 39240187
AN - SCOPUS:85206958785
SN - 2161-2129
VL - 15
JO - mBio
JF - mBio
IS - 10
M1 - e0081024
ER -