PMID- 34095879
OWN - NLM
STAT- MEDLINE
DCOM- 20220301
LR  - 20240226
IS  - 2666-3791 (Electronic)
IS  - 2666-3791 (Linking)
VI  - 2
IP  - 5
DP  - 2021 May 18
TI  - Integrative metabolomics and transcriptomics identifies itaconate as an adjunct 
      therapy to treat ocular bacterial infection.
PG  - 100277
LID - 10.1016/j.xcrm.2021.100277 [doi]
LID - 100277
AB  - The eye is highly susceptible to inflammation-mediated tissue damage evoked 
      during bacterial infection. However, mechanisms regulating inflammation to 
      protect the eye remain elusive. Here, we used integrated metabolomics and 
      transcriptomics to show that the immunomodulatory metabolite itaconate and 
      immune-responsive gene 1 (Irg1) are induced in bacterial (Staphylococcus 
      aureus)-infected mouse eyes, bone-marrow-derived macrophages (BMDMs), and Muller 
      glia. Itaconate levels are also elevated in the vitreous of patients with 
      bacterial endophthalmitis. Irg1 deficiency in mice led to increased ocular 
      pathology. Conversely, intraocular administration of itaconate protects both 
      Irg1(-/-) and wild-type mice from bacterial endophthalmitis by reducing 
      inflammation, bacterial burden, and preserving retinal architecture and visual 
      function. Notably, itaconate exerts synergistic effects with antibiotics. The 
      protective, anti-inflammatory effects of itaconate are mediated via activation of 
      NRF2/HO-1 signaling and inhibition of NLRP3 inflammasome. Collectively, our study 
      demonstrates the Irg1/itaconate axis is a regulator of intraocular inflammation 
      and provides evidence for using itaconate, along with antibiotics, to treat 
      bacterial infections.
CI  - (c) 2021 The Author(s).
FAU - Singh, Sukhvinder
AU  - Singh S
AD  - Department of Ophthalmology, Visual and Anatomical Sciences, Kresge Eye 
      Institute, Wayne State University School of Medicine, Detroit, MI, USA.
FAU - Singh, Pawan Kumar
AU  - Singh PK
AD  - Department of Ophthalmology, Visual and Anatomical Sciences, Kresge Eye 
      Institute, Wayne State University School of Medicine, Detroit, MI, USA.
FAU - Jha, Alokkumar
AU  - Jha A
AD  - Cardiovascular Institute, Stanford University, Stanford, CA, USA.
AD  - Stanford Cancer Institute, Stanford University, CA, USA.
FAU - Naik, Poonam
AU  - Naik P
AD  - L.V. Prasad Eye Institute, Hyderabad, India.
FAU - Joseph, Joveeta
AU  - Joseph J
AD  - L.V. Prasad Eye Institute, Hyderabad, India.
FAU - Giri, Shailendra
AU  - Giri S
AD  - Department of Neurology, Henry Ford Health System, Detroit, MI, USA.
FAU - Kumar, Ashok
AU  - Kumar A
AD  - Department of Ophthalmology, Visual and Anatomical Sciences, Kresge Eye 
      Institute, Wayne State University School of Medicine, Detroit, MI, USA.
AD  - Department of Biochemistry, Microbiology, and Immunology, Wayne State University 
      School of Medicine, Detroit, MI, USA.
LA  - eng
GR  - R01 EY026964/EY/NEI NIH HHS/United States
GR  - R01 EY027381/EY/NEI NIH HHS/United States
GR  - R21 AI140033/AI/NIAID NIH HHS/United States
GR  - P30 EY004068/EY/NEI NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
DEP - 20210518
PL  - United States
TA  - Cell Rep Med
JT  - Cell reports. Medicine
JID - 101766894
RN  - 0 (Inflammasomes)
RN  - 0 (NF-E2-Related Factor 2)
RN  - 0 (Succinates)
RN  - Q4516562YH (itaconic acid)
MH  - Animals
MH  - Eye Infections, Bacterial/metabolism
MH  - Inflammasomes/*drug effects/metabolism
MH  - Inflammation/*drug therapy/metabolism
MH  - Macrophages/drug effects
MH  - Metabolomics/methods
MH  - Mice, Inbred C57BL
MH  - Mice, Transgenic
MH  - NF-E2-Related Factor 2/drug effects/genetics
MH  - Signal Transduction/drug effects
MH  - Staphylococcal Infections/*drug therapy/metabolism
MH  - Staphylococcus aureus/genetics
MH  - Succinates/*pharmacology
MH  - Transcriptome/*drug effects/immunology
MH  - Mice
PMC - PMC8149370
OTO - NOTNLM
OT  - Irg1
OT  - NLRP3
OT  - NRF2/HO1
OT  - S. aureus
OT  - endophthalmitis
OT  - eye
OT  - inflammation
OT  - itaconate
OT  - retina
COIS- The authors declare no competing interests.
EDAT- 2021/06/08 06:00
MHDA- 2021/06/08 06:01
PMCR- 2021/05/18
CRDT- 2021/06/07 06:14
PHST- 2020/08/18 00:00 [received]
PHST- 2020/12/13 00:00 [revised]
PHST- 2021/04/19 00:00 [accepted]
PHST- 2021/06/07 06:14 [entrez]
PHST- 2021/06/08 06:00 [pubmed]
PHST- 2021/06/08 06:01 [medline]
PHST- 2021/05/18 00:00 [pmc-release]
AID - S2666-3791(21)00105-1 [pii]
AID - 100277 [pii]
AID - 10.1016/j.xcrm.2021.100277 [doi]
PST - epublish
SO  - Cell Rep Med. 2021 May 18;2(5):100277. doi: 10.1016/j.xcrm.2021.100277. 
      eCollection 2021 May 18.