Abstract
Intracerebral hemorrhage (ICH) is a devastating sub-type of stroke with no proven treatment. Given the emerging role of Galectin-1 and Galectin-3 in neuroimmune responses, the objective of the current manuscript is to elucidate hemorrhagic-injury induced modulation and cellular expression of Galectin-1 and Galectin-3 in the brain in a pre-clinical model of ICH. To address this, ICH was induced in male CD1 mice by collagenase injection method. Western blotting as well as Immunofluorescence staining was performed to characterize the temporal expression pattern as well as cellular localization of Galectin-1 and Galectin-3 after ICH. Further, genetic studies were conducted to assess the functional role of Galectin-1 and Galectin-3 in inflammatory response employing a murine macrophage cell line, RAW 264.7. Galectin-1 and Galectin-3 exhibited very profound and increased expression from day 3 to day 7-post-injury, in the perihematomal brain region after ICH in comparison to Sham. Further, Galectin-1 expression was mostly observed in GFAP-positive astrocytes whereas Galectin-3 expression was observed mostly in Iba1-positive microglia/macrophages as well as CD16/32 (M1 microglial/macrophage marker)-positive cells. Moreover, genetic studies revealed a negative regulatory role of both Galectin-1 and Galectin-3 in the release of a proinflammatory cytokine, IL-6 from RAW 264.7 cells depending on the stimulus. Altogether, the present manuscript demonstrates for the first time, increased expression as well as cellular localization of Galectin-1 and Galectin-3 in the perihematomal brain regions after ICH. In addition, the manuscript raises the potential of Galectin-1 and Galectin-3 in modulating glial responses and thereby brain injury after ICH, warranting further investigation.
Highlights
Intracerebral hemorrhage is a fatal stroke subtype (Qureshi et al, 2001a) that accounts for an inhospital mortality rate and a disability rate of 40 and 80%, respectively (van Asch et al, 2010)
Given the emerging role of Galectin-1 and Galectin-3 in neuroimmune responses, the ipsilateral brain sections from sham or Intracerebral hemorrhage (ICH) mice were subjected to evaluation employing both western blotting and immunohistochemistry analysis at various time points ranging from day 1 through day 7 post surgery, a post-injury time period, which exhibited remarkable induction of both pro- as well as anti-inflammatory activation of microglia/macrophages as well as astrocytes after ICH (Sukumari-Ramesh et al, 2012b, 2016; Bonsack et al, 2016)
The induction of Galectin-3 (Figure 2) mirrored the Galectin-1 expression after ICH and Galectin-3 immunopositive cells were approximately 15, 28 and 24- fold higher on day 3, day 5, and day 7 post-ICH (Figure 2B) in comparison to sham and the western blotting followed by densitometry analysis confirmed the injury-induced increased expression of Galectin-3 after ICH (Figures 2C,D)
Summary
Intracerebral hemorrhage is a fatal stroke subtype (Qureshi et al, 2001a) that accounts for an inhospital mortality rate and a disability rate of 40 and 80%, respectively (van Asch et al, 2010). ICH is responsible for 10–15% of all strokes, and the worldwide incidence of ICH is 2 million cases per year (van Asch et al, 2010) with approximately 120,000 cases per year in the United States. Neuroinflammation characterized by the activation of microglia, the neuroimmune cells of the CNS, is a key contributor of ICH-induced secondary brain injury and loss of neurological function (Wang and Dore, 2007; Carmichael et al, 2008; Wang, 2010). The proinflammatory activation of microglia after ICH correlates with blood-brain barrier damage, brain swelling/edema, hematoma expansion, neurological deterioration, and poor functional recovery (Platt et al, 1998; Hickenbottom et al, 1999; Leira et al, 2004; Zhao et al, 2007). Inflammatory response after ICH regulates the brain recruitment of blood-derived monocytes/macrophages that are known to regulate ICH-induced brain injury and thereby functional recovery (Tessier et al, 1997; Shiratori et al, 2010; Starossom et al, 2012)
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