PMID- 35488354
OWN - NLM
STAT- MEDLINE
DCOM- 20220503
LR  - 20220716
IS  - 1742-2094 (Electronic)
IS  - 1742-2094 (Linking)
VI  - 19
IP  - 1
DP  - 2022 Apr 29
TI  - TLR4 mutation protects neurovascular function and cognitive decline in high-fat 
      diet-fed mice.
PG  - 104
LID - 10.1186/s12974-022-02465-3 [doi]
LID - 104
AB  - BACKGROUND: Metabolic syndrome (MS) is defined as a low-grade proinflammatory 
      state in which abnormal metabolic and cardiovascular factors increase the risk of 
      developing cardiovascular disease and neuroinflammation. Events, such as the 
      accumulation of visceral adipose tissue, increased plasma concentrations of free 
      fatty acids, tissue hypoxia, and sympathetic hyperactivity in MS may contribute 
      to the direct or indirect activation of Toll-like receptors (TLRs), specifically 
      TLR4, which is thought to be a major component of this syndrome. Activation of 
      the innate immune response via TLR4 may contribute to this state of chronic 
      inflammation and may be related to the neuroinflammation and neurodegeneration 
      observed in MS. In this study, we investigated the role of TLR4 in the brain 
      microcirculation and in the cognitive performance of high-fat diet (HFD)-induced 
      MS mice. METHODS: Wild-type (C3H/He) and TLR4 mutant (C3H/HeJ) mice were 
      maintained under a normal diet (ND) or a HFD for 24 weeks. Intravital 
      video-microscopy was used to investigate the functional capillary density, 
      endothelial function, and endothelial-leukocyte interactions in the brain 
      microcirculation. Plasma concentrations of monocyte chemoattractant protein-1 
      (MCP-1), adipokines and metabolic hormones were measured with a multiplex 
      immunoassay. Brain postsynaptic density protein-95 and synaptophysin were 
      evaluated by western blotting; astrocytic coverage of the vessels, microglial 
      activation and structural capillary density were evaluated by 
      immunohistochemistry. RESULTS: The HFD-induced MS model leads to metabolic, 
      hemodynamic, and microcirculatory alterations, as evidenced by capillary 
      rarefaction, increased rolling and leukocyte adhesion in postcapillary venules, 
      endothelial dysfunction, and less coverage of astrocytes in the vessels, which 
      are directly related to cognitive decline and neuroinflammation. The same model 
      of MS reproduced in mice deficient for TLR4 because of a genetic mutation does 
      not generate such changes. Furthermore, the comparison of wild-type mice fed a 
      HFD and a normolipid diet revealed differences in inflammation in the cerebral 
      microcirculation, possibly related to lower TLR4 activation. CONCLUSIONS: Our 
      results demonstrate that TLR4 is involved in the microvascular dysfunction and 
      neuroinflammation associated with HFD-induced MS and possibly has a causal role 
      in the development of cognitive decline.
CI  - (c) 2022. The Author(s).
FAU - Obadia, Nathalie
AU  - Obadia N
AD  - Laboratory of Immunopharmacology, Oswaldo Cruz Institute, FIOCRUZ, Av. Brasil, 
      4365, Manguinhos, Rio de Janeiro, 21040-900, Brazil.
FAU - Andrade, Giulia
AU  - Andrade G
AD  - Laboratory of Immunopharmacology, Oswaldo Cruz Institute, FIOCRUZ, Av. Brasil, 
      4365, Manguinhos, Rio de Janeiro, 21040-900, Brazil.
FAU - Leardini-Tristao, Marina
AU  - Leardini-Tristao M
AD  - Laboratory of Immunopharmacology, Oswaldo Cruz Institute, FIOCRUZ, Av. Brasil, 
      4365, Manguinhos, Rio de Janeiro, 21040-900, Brazil.
FAU - Albuquerque, Leticia
AU  - Albuquerque L
AD  - Laboratory of Immunopharmacology, Oswaldo Cruz Institute, FIOCRUZ, Av. Brasil, 
      4365, Manguinhos, Rio de Janeiro, 21040-900, Brazil.
FAU - Garcia, Celina
AU  - Garcia C
AD  - Laboratory of Glial Cell Biology, Institute of Biomedical Sciences, Federal 
      University of Rio de Janeiro, Rio de Janeiro, Brazil.
FAU - Lima, Flavia
AU  - Lima F
AD  - Laboratory of Glial Cell Biology, Institute of Biomedical Sciences, Federal 
      University of Rio de Janeiro, Rio de Janeiro, Brazil.
FAU - Daleprane, Julio
AU  - Daleprane J
AD  - Interdisciplinary Nutrition Assessment Laboratory, Rio de Janeiro State 
      University, Rio de Janeiro, Brazil.
FAU - Castro-Faria-Neto, Hugo C
AU  - Castro-Faria-Neto HC
AD  - Laboratory of Immunopharmacology, Oswaldo Cruz Institute, FIOCRUZ, Av. Brasil, 
      4365, Manguinhos, Rio de Janeiro, 21040-900, Brazil.
FAU - Tibirica, Eduardo
AU  - Tibirica E
AD  - National Institute of Cardiology, Rio de Janeiro, Brazil.
FAU - Estato, Vanessa
AU  - Estato V
AUID- ORCID: 0000-0002-1581-9620
AD  - Laboratory of Immunopharmacology, Oswaldo Cruz Institute, FIOCRUZ, Av. Brasil, 
      4365, Manguinhos, Rio de Janeiro, 21040-900, Brazil. vanessaestato@gmail.com.
LA  - eng
PT  - Journal Article
DEP - 20220429
PL  - England
TA  - J Neuroinflammation
JT  - Journal of neuroinflammation
JID - 101222974
RN  - 0 (Tlr4 protein, mouse)
RN  - 0 (Toll-Like Receptor 4)
SB  - IM
MH  - Animals
MH  - *Cognitive Dysfunction/complications
MH  - Diet, High-Fat/adverse effects
MH  - Inflammation/metabolism
MH  - *Metabolic Syndrome/etiology
MH  - Mice
MH  - Mice, Inbred C3H
MH  - Microcirculation
MH  - Mutation
MH  - Toll-Like Receptor 4/genetics/metabolism
PMC - PMC9052472
OTO - NOTNLM
OT  - Brain microcirculation
OT  - High-fat diet consumption
OT  - Neuroinflammation, glial cells
OT  - TLR4
COIS- The authors declare no competing interests.
EDAT- 2022/05/01 06:00
MHDA- 2022/05/04 06:00
PMCR- 2022/04/29
CRDT- 2022/04/30 00:02
PHST- 2021/10/04 00:00 [received]
PHST- 2022/04/19 00:00 [accepted]
PHST- 2022/04/30 00:02 [entrez]
PHST- 2022/05/01 06:00 [pubmed]
PHST- 2022/05/04 06:00 [medline]
PHST- 2022/04/29 00:00 [pmc-release]
AID - 10.1186/s12974-022-02465-3 [pii]
AID - 2465 [pii]
AID - 10.1186/s12974-022-02465-3 [doi]
PST - epublish
SO  - J Neuroinflammation. 2022 Apr 29;19(1):104. doi: 10.1186/s12974-022-02465-3.