Experimental Stroke-Induced Changes in the Bone Marrow Reveal Complex Regulation of Leukocyte Responses

Abstract

Stroke induces a systemic response that involves rapid activation of inflammatory cascades, followed later by immunodepression. Experimental stroke-induced responses in the bone marrow, which is the primary source of circulating monocytes and granulocytes, have not been investigated previously. We show that cerebral ischaemia induced early (4 hours) release of CXCR2-positive granulocytes from the bone marrow, which was associated with rapid systemic upregulation of CXCL1 (a ligand for CXCR2) and granulocyte-colony-stimulating factor, a key cytokine involved in the mobilisation of bone marrow leukocytes. This process involves rapid activation of nuclear factor-jB and p38 mitogen-activated protein kinase in bone marrow myeloid cells. T-cell numbers in the bone marrow increased after stroke, and bone marrow cells did not show suppressed cytokine response to bacterial endotoxin stimulation in vitro. Stroke-induced laterality observed in the brain stem and in the bone marrow indicates direct involvement of the autonomic nervous system in stroke-induced cell mobilisation. We also show that systemic inflammatory changes and leukocyte responses in the bone marrow are profoundly affected by both anaesthetic and surgical stress. We conclude that stroke influences leukocyte responses in the bone marrow through multiple mechanisms and suggest that preclinical studies should take into consideration the effect of surgical manipulation in experimental models of stroke.

Altered Circulating Leukocytes and Their Chemokines in a Clinical Trial of Therapeutic Hypothermia for Neonatal Hypoxic Ischemic Encephalopathy*

“…In human adults with severe stroke, lymphocyte counts decreased over days 1 to 4, whereas neutrophil and monocyte counts increased but were profoundly deactivated compared to patients with smaller infarcts (37). Thus, there is strong evidence in both animals and humans that the decreased numbers of circulating leukocytes in severe HI are clinically important and correlate with functional immune compromise (31,38).…”

“…Circulating leukocytes and monocytes respond within 30-60 minutes after middle cerebral artery occlusion (27)(28)(29), whereas leukocyte recruitment from bone marrow takes more time, up to 4 hours after acute experimental stroke (27)(28)(29)(30)(31). Although early elevation of circulating WBC after HI insult may augment CNS injury (32,33), prolonged immunosuppression, characterized by lymphopenia and increased plasma IL-10, is associated with immune paralysis and worse outcome in both human adult stroke and animal models of traumatic brain injury, even with hypothermia (15,34,35).…”

Experimental Intracerebral Hemorrhage: Avoiding Pitfalls in Translational Research

“…For example, a study comparing bone marrow response to experimental stroke, sham surgery, and administration of isofluorane alone found systemic inflammatory changes and leukocyte responses in the bone marrow to be markedly affected even with isofluorane alone (Denes et al, 2011). The effect of isofluorane on various leukocyte populations occurs early within the first 20 to 30 minutes of anesthesia (Denes et al, 2011). While use of anesthesia is unavoidable in experimental ICH, this study highlights the need to account for the role of surgery and anesthesia when interpreting any results derived from such studies.…”

Evolution of microglial activation in ischaemic core and peri-infarct regions after stroke: A PET study with the TSPO molecular imaging biomarker [ C]vinpocetine

“…In the infarct region microglial activation starts hours after insult and the activated microglial cells transform into phagocytes within days after injury [58]. Already 48 to 73 h after the injury, the resident microglial population in the affected region shows an intensive proliferating activity [59]. The microglial activation is not showing identical dynamics in the ischaemic core and the peri-infarct zone: whereas activated microglia appears within 3 days after injury in the boundary zone of the infarct, in the core region it is observed only from the seventh day on [60], whereas it was absent until that time [28].…”