Involvement of CXCL1/CXCR2 During Microglia Activation Following Inflammation-Sensitized Hypoxic-Ischemic Brain Injury in Neonatal Rats

Abstract

Background: Microglia are key mediators of inflammation during perinatal brain injury. As shown experimentally after inflammation-sensitized hypoxic ischemic (HI) brain injury, microglia are activated into a pro-inflammatory status 24 h after HI involving the NLRP3 inflammasome pathway. The chemokine (C-X-C motif) ligand 1 (CXCL1), and its cognate receptor, CXCR2, have been shown to be involved in NLRP3 activation, although their specific role during perinatal brain injury remains unclear. In this study we investigated the involvement of CXCL1/CXCR2 in brain tissue and microglia and brain tissue after inflammation-sensitized HI brain injury of newborn rats. Methods: Seven-day old Wistar rat pups were either injected with vehicle (NaCl 0.9%) or E. coli lipopolysaccharide (LPS), followed by left carotid ligation combined with global hypoxia (8% O 2 for 50 min). Pups were randomized into four different treatment groups: (1) Sham group ( n = 21), (2) LPS only group ( n = 20), (3) Veh/HI group ( n = 39), and (4) LPS/HI group ( n = 42). Twenty-four hours post hypoxia transcriptome and gene expression analysis were performed on ex vivo isolated microglia cells in our model. Additionally protein expression was analyzed in different brain regions at the same time point. Results: Transcriptome analyses showed a significant microglial upregulation of the chemokine CXCL1 and its receptor CXCR2 in the LPS/HI group compared with the other groups. Gene expression analysis showed a significant upregulation of CXCL1 and NLRP3 in microglia cells after inflammation-sensitized hypoxic-ischemic brain injury. Additionally, protein expression of CXCL1 was significantly upregulated in cortex of male pups from the LPS/HI group. Conclusion: These results indicate that the CXCL1/CXCR2 pathway may be involved during pro-inflammatory microglia activation following inflammation-sensitized hypoxic-ischemic brain injury in neonatal rats. This may lead to new treatment options altering CXCR2 activation early after HI brain injury.

MicroRNA-532-5p protects against cerebral ischemia-reperfusion injury by directly targeting CXCL1

“…CXCL1 is known to be a crucial mediator in inflammation and organ injury [ 27 ], and CXCR2 is the downstream protein of CXCL1 [ 28 , 29 ]. In a previous study, CXCL1/CXCR2 pathway could lead to the injury of brain tissues [ 15 ]. Our research was consistent to the previous reports, suggesting that miR-532-5p could reverse OGD/R-induced cell growth inhibition via mediation of CXCL1/CXCR2 pathway.…”

“…In addition, CXCL1 could modulate inflammation and cancer progression [ 14 ]. Meanwhile, CXCL1 levels are upregulated in hypoxic-Ischemic brain Injury [ 15 ]; however, the association between miR-532-5p and CXCL1 in CI/RI is unclear.…”

CXCL1/CXCR2 is Involved in White Matter Injury in Neonatal Rats via the Gut-Brain Axis

“…CXCL1 has also been shown to play a critical role in producing reactive oxygen species, which consequently regulate further in ammation [14]. Furthermore, the CXCL1/CXCR2 pathway may be involved in in ammation-induced hypoxic-ischemic brain injury (HIBI) in neonatal rats and pro-in ammatory microglial activation [15].…”

Comparison of the Effects of Chemokine Receptors CXCR2 and CXCR3 Pharmacological Modulation in Neuropathic Pain Model—In Vivo and In Vitro Study

“…These proteins play a key role in the initiation and regulation of inflammation and are essential for neuronal transmission and cell-to-cell communication [33]. In the nervous system, CXCR2 is constitutively expressed on neurons and astrocytes [34,35], is upregulated in infiltrating macrophages and neutrophils [36,37] and in microglia activated in response to brain or nerve injury [34,38,39], and it is strongly associated with neutrophil chemotaxis [40][41][42]. CXCR3 is also expressed on various cell types, such as neurons, monocytes, lymphocytes (including CD4 + and CD8 + T and B cells), natural killer cells, and dendritic cells [20,[42][43][44][45][46][47].…”