Modulation of microglial phenotypes improves sepsis-induced hippocampus-dependent cognitive impairments and decreases brain inflammation in an animal model of sepsis

Abstract

Background: In order to modulate microglial phenotypes in vivo, M1 microglia were depleted by administration of gadolinium chloride and the expression of M2 microglia was induced by IL-4 administration in an animal model of sepsis to better characterize the role of microglial phenotypes in sepsis-induced brain dysfunction. Methods: Wistar rats were submitted to sham or cecal ligation and perforation (CLP) and treated with IL-4 or GdCl3. Animals were submitted to behavioral tests 10 days after surgery. In a separated cohort of animals at 24 h, 3 and 10 days after surgery, hippocampus was removed and cytokine levels, M1/M2 markers and CKIP-1 levels were determined. Results: Modulation of microglia by IL-4 and GdCl3 was associated with an improvement in long-term cognitive impairment. When treated with IL-4 and GdCl3, the reduction of pro-inflammatory cytokines was apparent in almost all analyzed time points. Additionally, CD11b and iNOS were increased after CLP at all time points, and both IL-4 and GdCl3 treatments were able to reverse this. There was a significant decrease in CD11b gene expression in the CLP+GdCl3 group. IL-4 treatment was able to decrease iNOS expression after sepsis. Furthermore, there was an increase of CKIP-1 in the hippocampus of GdCl3 and IL-4 treated animals 10 days after CLP induction. Conclusions: GdCl3 and IL-4 are able to manipulate microglial phenotype in an animal models of sepsis, by increasing the polarization toward an M2 phenotype IL-4 and GdCl3 treatment was associated with decreased brain inflammation and functional recovery.

Erbin protects against sepsis-associated encephalopathy by attenuating microglia pyroptosis via IRE1α/Xbp1s-Ca2+ axis

“…The hippocampus is one of the brain structures that is more sensitive to the cognitive dysfunction caused by sepsis [ 43 ]. Damage to hippocampal CA1 and CA3 regions, critical brain regions for learning and memory, may lead to cognitive impairment [ 44 ].…”

Mitochondrial protective effects caused by the administration of mefenamic acid in sepsis

“…This increase in cytokines in the CNS maybe related to the breakdown of the BBB, increasing the passage of inflammatory mediators into the brain tissue, stimulating microglial cells [ 30 – 33 ]. In another study, high concentrations of IL-1β and TNF-α and a large number of cells labeled with IBA-1 were found in the early stages of sepsis in an animal model of sepsis induced by the CLP surgery [ 34 , 35 ]. It is known that the increase in IL-18 is related to septic shock and tissue damage, and its control is critical [ 36 ].…”

Targeted rescue of synaptic plasticity improves cognitive decline after severe systemic inflammation

“…In parallel, anti-inflammatory mediators, e.g. lipocalin2 (LCN2) are induced to counteract LPS-induced neuroinflammation 16,54,55 . Even if experimental systemic LPS challenge may not completely mimick polymicrobial sepsisthese observations likely reflect important mechanistic aspects of CNS neuroinflammation since this proinflammatory profile has also been identified in other infectious rodent models, e.g.…”

“…It is conceivable that severe systemic inflammation leads to activation of cerebral immune cells, e.g. microglia thereby inducing a pathological proinflammatory milieu in the brain (Mazeraud et al, 2020;Michels et al, 2020;Semmler et al, 2008;Shemer et al, 2020;Trzeciak et al, 2019;Widmann and Heneka, 2014;Zrzavy et al, 2019). However, the pathophysiology of SAE is only incompletely understood and causal therapeutic options are missing.…”