TY - JOUR
T1 - Metallothionein 3-Zinc Axis Suppresses Caspase-11 Inflammasome Activation and Impairs Antibacterial Immunity
AU - Chowdhury, Debabrata
AU - Gardner, Jason C.
AU - Satpati, Abhijit
AU - Nookala, Suba
AU - Mukundan, Santhosh
AU - Porollo, Aleksey
AU - Landero Figueroa, Julio A.
AU - Subramanian Vignesh, Kavitha
N1 - Publisher Copyright:
Copyright © 2021 Chowdhury, Gardner, Satpati, Nookala, Mukundan, Porollo, Landero Figueroa and Subramanian Vignesh.
PY - 2021/11/12
Y1 - 2021/11/12
N2 - Non-canonical inflammasome activation by mouse caspase-11 (or human CASPASE-4/5) is crucial for the clearance of certain gram-negative bacterial infections, but can lead to severe inflammatory damage. Factors that promote non-canonical inflammasome activation are well recognized, but less is known about the mechanisms underlying its negative regulation. Herein, we identify that the caspase-11 inflammasome in mouse and human macrophages (Mϕ) is negatively controlled by the zinc (Zn2+) regulating protein, metallothionein 3 (MT3). Upon challenge with intracellular lipopolysaccharide (iLPS), Mϕ increased MT3 expression that curtailed the activation of caspase-11 and its downstream targets caspase-1 and interleukin (IL)-1β. Mechanistically, MT3 increased intramacrophage Zn2+ to downmodulate the TRIF-IRF3-STAT1 axis that is prerequisite for caspase-11 effector function. In vivo, MT3 suppressed activation of the caspase-11 inflammasome, while caspase-11 and MT3 synergized in impairing antibacterial immunity. The present study identifies an important yin-yang relationship between the non-canonical inflammasome and MT3 in controlling inflammation and immunity to gram-negative bacteria.
AB - Non-canonical inflammasome activation by mouse caspase-11 (or human CASPASE-4/5) is crucial for the clearance of certain gram-negative bacterial infections, but can lead to severe inflammatory damage. Factors that promote non-canonical inflammasome activation are well recognized, but less is known about the mechanisms underlying its negative regulation. Herein, we identify that the caspase-11 inflammasome in mouse and human macrophages (Mϕ) is negatively controlled by the zinc (Zn2+) regulating protein, metallothionein 3 (MT3). Upon challenge with intracellular lipopolysaccharide (iLPS), Mϕ increased MT3 expression that curtailed the activation of caspase-11 and its downstream targets caspase-1 and interleukin (IL)-1β. Mechanistically, MT3 increased intramacrophage Zn2+ to downmodulate the TRIF-IRF3-STAT1 axis that is prerequisite for caspase-11 effector function. In vivo, MT3 suppressed activation of the caspase-11 inflammasome, while caspase-11 and MT3 synergized in impairing antibacterial immunity. The present study identifies an important yin-yang relationship between the non-canonical inflammasome and MT3 in controlling inflammation and immunity to gram-negative bacteria.
KW - MT3
KW - caspase-11 non-canonical inflammasome
KW - innate immunity
KW - macrophage
KW - metallothionein
KW - non-canonical inflammasome
KW - zinc
UR - http://www.scopus.com/inward/record.url?scp=85120427225&partnerID=8YFLogxK
U2 - 10.3389/fimmu.2021.755961
DO - 10.3389/fimmu.2021.755961
M3 - Article
C2 - 34867993
AN - SCOPUS:85120427225
SN - 1664-3224
VL - 12
JO - Frontiers in Immunology
JF - Frontiers in Immunology
M1 - 755961
ER -