Interleukin 8 (CXCL8)-CXC chemokine receptor 2 (CXCR2) axis contributes to MiR-4437-associated recruitment of granulocytes and natural killer cells in ischemic stroke
Introduction
Accumulating evidence has indicated that the immune system and inflammation play a leading role in ischemic stroke, particularly in brain tissue damage, progression of ischemic lesions, and tissue repair (Burrows et al., 2016; Ma et al., 2015; Picascia et al., 2015). Typically following ischemic stroke there is a rapid infiltration of granulocytes, particularly neutrophils, which can result in blood-brain barrier disruption, cerebral edema, and brain injury (Jickling et al., 2015). In addition to granulocytes, natural killer (NK) cells, which are key members of the innate immune system, accumulate in the ischemic hemisphere (Gan et al., 2014; Zhang et al., 2014). The NK cells determine the size of the brain infarct (Gan et al., 2014) and are responsible for ischemia-related neuronal death by secreting interferon (IFN)-γ (Gan et al., 2014; Zhang et al., 2014). On the other hand, chemokines are a class of pro-inflammatory cytokines that have the ability to attract and activate leukocytes. In the highly inflammatory sites of acute ischemic stroke, chemokines are mainly generated by microglial cells and infiltrating immune cells, resulting in an exacerbated inflammatory cascade and brain injury (Lee et al., 2015; Remus et al., 2015).
The CXC chemokine receptor 2 (CXCR2) is a regulator of neutrophil homeostasis (Veenstra and Ransohoff, 2012). In experimental mice with ischemic stroke, it has been demonstrated that a vast amount of CXCR2+ granulocytes are activated and released from the bone marrow (Denes et al., 2011). Furthermore, CXCR2 blockade mitigated the neurological deficits and reduced the infarct volume (Herz et al., 2015; Sousa et al., 2013). Thus, CXCR2-positive granulocytes play an important role in ischemic brain injury. However, no study to date has evaluated the expression of CXCR2 in patients with stroke. Additionally, in ischemic stroke the expression of interleukin-8 (CXCL8), one of the ligands of CXCR2, is controversial. In particular, several previous studies have indicated no change in CXCL8 levels in patients with stroke (Montaner et al., 2003; Pedersen et al., 2004), while others demonstrated increased CXCL8 levels (Al-Bahrani et al., 2007; Grau et al., 2001a, b). Furthermore, the involvement of the CXCL8-CXCR2 chemotactic axis in the recruitment of immune cells in ischemic stroke is not well understood.
This study aimed to investigate the effect and underlying mechanism of the CXCL8-CXCR2 chemotactic axis in ischemic stroke.
Section snippets
Patients
A total of 140 patients experiencing the first week of their first-ever acute ischemic stroke were recruited at the First Affiliated Hospital of Zhengzhou University from 25 June 2015 to 20 June 2018. All enrolled patients signed a written informed consent, and all experimental protocols were approved by the Ethics Committees of the First Affiliated Hospital of Zhengzhou University. Patients were excluded if they had infections, autoimmune diseases, cancers, or other conditions that could
CXCL8-CXCR2 chemotactic axis is upregulated in the peripheral blood of patients with ischemic stroke
To analyze the expression of CXCR2 mRNA in patients with ischemic stroke, the GEO database was explored. The GSE16561 cluster analysis dataset (Barr et al., 2010) demonstrated that CXCR2 expression was increased in patients with stroke (Fig. 1A), while the GSE22255 dataset (Krug et al., 2012) indicated no statistical difference between patients and healthy donors (data not show). Peripheral leucocytes were subsequently collected from 20 patients with ischemic stroke and 10 matched healthy
Discussion
Accumulated evidence has suggested that ischemic stroke is a systemic inflammatory disease involving various immunocytes and cytokines. More specifically, granulocytes, especially neutrophils, are among the first responders following infection or injury, including stroke, which is indicated by their rapid migration to the affected tissues (Kim and Luster, 2015). The recruitment and activation of granulocytes play an important role in asthma (Bruijnzeel et al., 2015), chronic obstructive
Conclusions
In conclusion, the CXCL8-CXCR2 chemotactic axis played an important role in granulocyte and NK cell recruitment. MiR-4437, which is a negative regulator of CXCR2, might be a new target for ischemic stroke treatment. Serum CXCL8 levels could also be a potential prognostic factor for ischemic stroke.
Acknowledgments
This research did not receive any specificgrant from funding agencies in the public, commercial, or not-for-profit sectors.
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