PMID- 35301258
OWN - NLM
STAT- MEDLINE
DCOM- 20220414
LR  - 20220918
IS  - 2573-7732 (Electronic)
IS  - 2573-7732 (Linking)
VI  - 6
IP  - 3
DP  - 2022 Mar 17
TI  - NLRC4 Deficiency Leads to Enhanced Phosphorylation of MLKL and Necroptosis.
PG  - 243-252
LID - 10.4049/immunohorizons.2100118 [doi]
AB  - Hosts rely on the innate immune system to clear pathogens in response to 
      infection. Pathogen-associated molecular patterns bind to innate immune receptors 
      and engage activation of downstream signaling to initiate a host immune response 
      to fight infection. A key component of this innate response is programmed cell 
      death. Recent work has highlighted significant cross-talk and functional 
      redundancy between cell death pathways, leading to the discovery of PANoptosis, 
      an inflammatory programmed cell death pathway dependent on PANoptosomes, which 
      are innate immune danger-sensing complexes that activate inflammatory cell death 
      and contain caspases with or without inflammasome components and receptor 
      interacting protein homotypic interaction motif-containing proteins. Although 
      PANoptosis has been characterized in response to a growing number of pathogens, 
      inflammatory diseases, and cancer, its role and the functional consequences of 
      PANoptotic component modulation during NLR family CARD domain-containing protein 
      4 (NLRC4) activation by Pseudomonas aeruginosa infection remain unknown. In this 
      study, we show that P. aeruginosa can induce PANoptosis in mouse bone 
      marrow-derived macrophages (BMDMs). Only the combined deletion of caspase-1, -11, 
      -8, and RIPK3 protected mouse BMDMs from cell death. Moreover, we showed that 
      PANoptotic components act in a compensatory manner; in the absence of NAIP5 and 
      NLRC4 during P. aeruginosa challenge, activation of caspase-1, -3, -7, and -8 was 
      reduced, whereas alternative cell death molecules such as RIPK1 and MLKL were 
      activated in mouse BMDMs. Taken together, these data highlight the extensive 
      cross-talk between cell death signaling molecules and showcase the plasticity of 
      the system.
CI  - Copyright (c) 2022 The Authors.
FAU - Sundaram, Balamurugan
AU  - Sundaram B
AUID- ORCID: 0000-0002-1019-3681
AD  - Department of Immunology, St. Jude Children's Research Hospital, Memphis, TN.
FAU - Karki, Rajendra
AU  - Karki R
AUID- ORCID: 0000-0003-4436-9128
AD  - Department of Immunology, St. Jude Children's Research Hospital, Memphis, TN.
FAU - Kanneganti, Thirumala-Devi
AU  - Kanneganti TD
AUID- ORCID: 0000-0002-6395-6443
AD  - Department of Immunology, St. Jude Children's Research Hospital, Memphis, TN 
      devi.kanneganti@stjude.org.
LA  - eng
GR  - R35 CA253095/CA/NCI NIH HHS/United States
GR  - R01 AI101935/AI/NIAID NIH HHS/United States
GR  - R01 AI124346/AI/NIAID NIH HHS/United States
GR  - R37 AI101935/AI/NIAID NIH HHS/United States
GR  - R01 AI160179/AI/NIAID NIH HHS/United States
GR  - R01 AR056296/AR/NIAMS NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
DEP - 20220317
PL  - United States
TA  - Immunohorizons
JT  - ImmunoHorizons
JID - 101708159
RN  - 0 (Inflammasomes)
RN  - 0 (Naip5 protein, mouse)
RN  - 0 (Neuronal Apoptosis-Inhibitory Protein)
RN  - EC 2.7.- (MLKL protein, mouse)
RN  - EC 2.7.- (Protein Kinases)
RN  - EC 3.4.22.- (Caspases)
SB  - IM
MH  - Animals
MH  - Caspases/metabolism
MH  - Inflammasomes/metabolism
MH  - *Macrophages
MH  - Mice
MH  - *Necroptosis
MH  - Neuronal Apoptosis-Inhibitory Protein/metabolism
MH  - Phosphorylation
MH  - Protein Kinases/genetics/metabolism
PMC - PMC8996759
MID - NIHMS1791283
COIS- Competing financial interests The authors declare no competing financial 
      interests.
EDAT- 2022/03/19 06:00
MHDA- 2022/04/15 06:00
PMCR- 2022/09/17
CRDT- 2022/03/18 05:40
PHST- 2022/01/03 00:00 [received]
PHST- 2022/02/28 00:00 [accepted]
PHST- 2022/03/18 05:40 [entrez]
PHST- 2022/03/19 06:00 [pubmed]
PHST- 2022/04/15 06:00 [medline]
PHST- 2022/09/17 00:00 [pmc-release]
AID - immunohorizons.2100118 [pii]
AID - 10.4049/immunohorizons.2100118 [doi]
PST - epublish
SO  - Immunohorizons. 2022 Mar 17;6(3):243-252. doi: 10.4049/immunohorizons.2100118.