CCR2-dependent monocytes/macrophages exacerbate acute brain injury but promote functional recovery after ischemic stroke in mice

Abstract

Rationale: Peripheral blood monocytes are recruited into the ischemic brain and transform into macrophages after stroke. Nevertheless, the exact role of CCR2-dependent monocytes/macrophages in brain injury after stroke remains elusive.Methods: We used CCR2 knockout (KO) mice and the CCR2 pharmacological inhibitor, propagermanium (PG), to address the role of CCR2-dependent monocytes/macrophages in the acute stage and neurological functional recovery after middle cerebral artery (MCA) occlusion and reperfusion.Results: CCR2 KO resulted in smaller infarct size and lower mortality than in wild type (WT) mice, when measured 3 days after stroke. However, from 5 to 28 days after stroke, the KO mice had higher mortality and showed no obvious neurological functional recovery. In addition, WT mice treated with PG had similar stroke outcomes compared with CCR2 KO, as measured by T2 weighted MRI. Flow cytometry and real-time PCR analyses suggest that monocyte-derived macrophages (MoDMs) in the stroke brains mainly polarized to pro-inflammatory macrophages at the early stage, but gradually switched to anti-inflammatory macrophages at 7 days after stroke. In addition, adoptive transfer of anti-inflammatory macrophages into CCR2 KO mice at 4 and 6 days after stroke alleviated mortality and promoted neurological recovery.Conclusion: CCR2-dependent monocytes/macrophages are a double-edged sword; they worsen acute brain injury, but are essential for neurological recovery by promoting anti-inflammatory macrophage polarization.

Enhancing the Therapeutic Potential of CCL2-Overexpressing Mesenchymal Stem Cells in Acute Stroke

“…Previously studies suggest that increased CCL2 levels in stroke exacerbate neuro-inflammation and subsequent brain injury, thereby increasing stroke volume and resulting in poor prognosis [ 21 , 22 ]. However, recent studies show that CCL2/CCR2 interaction positively affects functional recovery from stroke [ 23 , 24 ], and other studies confirm that CCL2 promotes the homing of CCR2-expressing stem cells from the bone marrow to the damaged brain, which contributes to brain repair following stroke [ 20 , 25 , 26 ]. Additionally, this interaction promotes intravascular migration of stem cells into the injury sites and is essential for the therapeutic homing of CCR2-expressing stem cells [ 6 , 7 , 11 , 27 , 28 , 29 ].…”

“…In the present study, the results showed that transplantation of CCL2-overexpressing hUC-MSCs decreased neuro-inflammation accompanied by a decreased M1 population and increased M2 population relative to those in other groups, especially naïve hUC-MSCs. Therefore, the sustained upregulation of CCL2 for up to 28 days of the post-stroke delayed phase following CCL2-overexpressing hUC-MSCs transplantation might contribute to neurological recovery via CCL2/CCR2-dependent microglia/macrophage status based on the dominant pro-inflammatory phenotype observed in the acute phase versus the dominant anti-inflammatory phenotype in delayed phase after stroke [ 24 , 46 ].…”

Simultaneous targeting of mitochondria and monocytes enhances neuroprotection against ischemia–reperfusion injury

“…The role of CCR2-mediated inflammation after cerebral IR injury has been demonstrated in experimental animals 3,24 ; however, contradicting results that a selective CCR2 antagonist exacerbated the IR injury have been also reported 25 . Resent reports have shown that CCR2-dependent recruitment of monocytes/macrophages is a double-edge sword; they exacerbate acute brain injury but, on the other hand, promote the recovery of neurological functions because inflammatory macrophages recruited by a CCR2-dependent mechanism differentiate into reparative macrophages in the later phase after IR injury 26 . In this study, deletion of CCR2 decreased the infarct size 24 and 72 h after reperfusion accompanied with decreased accumulation of inflammatory monocytes in the injured brain.…”

Chemokine CCL2 contributes to BBB disruption via the p38 MAPK signaling pathway following acute intracerebral hemorrhage

“…13,15,28 However, the detailed mechanism by which elevated CCL2 is involved in BBB compromise after ICH has not been clearly identified. To clarify the potential mechanism by which CCL2 contributes to BBB disruption, the colocation of CCR2 and p-p38 MAPK was detected by triple immunofluorescence staining, and our F I G U R E 6 Colocation of the CCL2 receptor and p-p38 MAPK in vivo.…”

“…Until now, almost all evidence has shown that CCL2 plays a vital role in cerebral ischemic stroke. 13,15,28 However, the detailed mechanism by which elevated CCL2 is involved in BBB compromise after ICH has not been clearly identified. In our study, BBB disruption after ICH may have resulted from excessive p-p38 MAPK and AQP4 overexpression.…”