Role of Spleen-Derived Monocytes/Macrophages in Acute Ischemic Brain Injury

Abstract

Monocytes/macrophages (MMs), mononuclear phagocytes, have been implicated in stroke-induced inflammation and injury. However, the presence of pro-inflammatory Ly-6Chigh and antiinflammatory Ly-6Clow monocyte subsets raises uncertainty regarding their role in stroke pathologic assessment. With recent identification of the spleen as an immediate reservoir of MMs, this current study addresses whether the spleen-derived MMs are required for stroke pathologic assessment. We observed that the spleen was contracted in poststroke animals and the contraction was accompanied by decreased number of Ly-6Chigh and Ly-6Clow subsets in the spleen. The deployment of these subsets from the spleen temporally coincided with respective increases in the ischemic brain. Compared to mice with the spleen, mice receiving a splenectomy just before the stroke displayed less accumulation of Ly-6Chigh and Ly-6Clow MMs in the brain. Despite the reduced accumulation of both subsets, infarct size and swelling were not reduced in the asplenic mice. The dissociative findings of infarct size and extent of MM infiltration in the postischemic brain indicate minimal involvement of spleen-derived total MMs in acute infarct development. Selective Ly-6Chigh or Ly-6Clow MM targeting is suggested to address the contribution of the individual subset to acute stroke pathologic assessment.

Microglia and Monocyte-Derived Macrophages in Stroke

“…Alterations of peripheral immunity are also associated with atrophy of lymphatic organs, such as the spleen and thymus. This type of atrophy was accompanied by a reduced number of leukocytes in the spleen and an early transient increased number of leukocytes in the blood followed by a sharp reduction, demonstrating the deployment of immune cells into the circulatory system in response to stroke [25,26]. The reduced number of leukocytes in the periphery was attributed to immune cell migration to injured sites as the reduction of peripheral immune cells in the spleen and blood temporally coincided with the increased appearance of immune cells in the stroked brain [8,25].…”

“…The trafficking of immune cells in the poststroke brain is both temporally and spatially coordinated [8,25,27,28]. With an early rise of resident microglia after stroke, peripheral immune cells, including monocytes/macrophages, myeloid dendritic cells, and neutrophils, appear in the brain within 1 day poststroke, peak in number at 3 days poststroke, and remain sustained until 7 days poststroke.…”

“…The role of the spleen in cerebral ischemia has also been investigated. Both clinical and animal studies have demonstrated transient reduction in spleen size following stroke, which has been attributed to the poststroke deployment of splenocytes, including monocytes [25,[83][84][85]. The extent of spleen atrophy is associated with the severity of stroke-induced brain injury, leading to the view that the spleen plays a contributory role in stroke pathology [26,86].…”

“…The extent of spleen atrophy is associated with the severity of stroke-induced brain injury, leading to the view that the spleen plays a contributory role in stroke pathology [26,86]. Increased apoptosis in the spleen, albeit controversial (see Kim et al [25]), and cell release from the spleen are related to reduced spleen size [26]. Others have also reported that splenectomy or splenic irradiation reduces ischemic injury in animal models of stroke [87][88][89].…”

“…While these data provided a rationale for targeting the spleen as a therapeutic strategy for patients with stroke, there are reports that argue against this approach. Kim et al [25] addressed the role of splenic monocytes in ischemic stroke. In this study, pro-and antiinflammatory monocyte subsets were longitudinally determined at acute and subacute phases of ischemic stroke from 1 h to 7 days poststroke in the spleen, blood, bone marrow, and brain.…”