The absence of the CD163 receptor has distinct temporal influences on intracerebral hemorrhage outcomes

Abstract

Hemoglobin (Hb) toxicity precipitates secondary brain damage following intracerebral hemorrhage (ICH). CD163 is an anti-inflammatory Hb scavenger receptor and CD163-positive macrophages/microglia locally accumulate post-bleed, yet no studies have investigated the role of CD163 after ICH. ICH was induced in wildtype and CD163 mice and various anatomical and functional outcomes were assessed. At 3 d, CD163 mice have 43.4 ± 5.0% (p = 0.0002) and 34.8 ± 3.4% (p = 0.0003) less hematoma volume and tissue injury, respectively. Whereas, at 10 d, CD163 mice have 49.2 ± 15.0% larger lesions (p = 0.0385). An inflection point was identified, where CD163 mice perform better on neurobehavioral testing and have less mortality before 4 d, but increased mortality and worse function after 4 d (p = 0.0389). At 3 d, CD163 mice have less Hb, iron, and blood-brain barrier dysfunction, increased astrogliosis and neovascularization, and no change in heme oxygenase 1 (HO1) expression. At 10 d, CD163 mice have increased iron and VEGF immunoreactivity, but no significant change in HO1 or astrogliosis. These novel findings reveal that CD163 deficiency has distinct temporal influences following ICH, with early beneficial properties but delayed injurious effects. While it is unclear why CD163 deficiency is initially beneficial, the late injurious effects are consistent with the key anti-inflammatory role of CD163 in the recovery phase of tissue damage.

Acute Treatment With Gleevec Does Not Promote Early Vascular Recovery Following Intracerebral Hemorrhage in Adult Male Rats

“…The prevention of acute changes in vascular smooth muscle we previously reported appeared to be due in part to probable reductions in neuroinflammatory processes (Yang et al, 2016). Further, in CD163−/− mice there was a decreased acute (3 days) inflammatory response to ICH (Leclerc et al, 2018). Similarly, heme oxygenase 1 (HO-1) activation and overexpression in astrocytes improved BBB disruption after ICH, acutely (Chen-Roetling et al, 2015).…”

“…Most studies investigating the vascular effects of ICH focused on the components of the neurovascular unit (NVU), endothelia, astrocytes and pericytes, with an eye toward blood brain barrier (BBB) breakdown. The disruption of the BBB by ICH leads to numerous downstream (secondary) events including increased bleeding, neuroinflammation and edema formation (Yang et al, 1994;Chen-Roetling et al, 2015;Leclerc et al, 2018;Xu et al, 2019). An 11% reduction in vessel density and volume was reported adjacent to the ICH lesion using high resolution micro-computed tomography (Xie et al, 2012).…”

“…Further research is needed to clarify the mechanisms that impact the cerebrovascular network after ICH. A range of interventions have been applied to mitigate the neurobiological effects of ICH and its subsequent poor outcomes (Hatakeyama et al, 2013;Chen-Roetling et al, 2015;Yang et al, 2016;Leclerc et al, 2018;Xu et al, 2019). However, most of the interventions for ICH to date have been neuro-centric, that is, focused on neuroprotection.…”

MiRNA-494 enhances M1 macrophage polarization via Nrdp1 in ICH mice model

“…Macrophage M1/M2 polarization have been identified in various central nervous system diseases, such as traumatic brain injury, spinal cord injury, and ischemic stroke [25][26][27]. The activation of macrophages occurs in the hemorrhagic brain and leads to inflammatory damage following ICH [28][29][30]. However, the specific mechanisms underlying macrophage polarization following ICH have not been well studied.…”

Association of Brain CD163 Expression and Brain Injury/Hydrocephalus Development in a Rat Model of Subarachnoid Hemorrhage

“…Heme oxygenase-1 (HO-1) is a key enzyme of heme degradation and the haptoglobin/hemoglobin-CD163-HO-1 system represents a basic line of defense against hemoglobin neurotoxicity by facilitating hemoglobin removal (Thomsen et al, 2013 ). We and others have demonstrated that CD163 is expressed and contributes to hematoma clearance following ICH (Cao et al, 2016 ; Liu et al, 2017 ; Leclerc et al, 2018 ), but the functions of CD163 have not been investigated after SAH.…”