Streptococcus pneumoniae worsens cerebral ischemia via interleukin 1 and platelet glycoprotein Ibα.

OBJECTIVE: Bacterial infection contributes to diverse noninfectious diseases and worsens outcome after stroke. Streptococcus pneumoniae, the most common infection in patients at risk of stroke, is a major cause of prolonged hospitalization and death of stroke patients, but how infection impacts clinical outcome is not known. METHODS: We induced sustained pulmonary infection by a human S. pneumoniae isolate in naive and comorbid rodents to investigate the effect of infection on vascular and inflammatory responses prior to and after cerebral ischemia. RESULTS: S. pneumoniae infection triggered atherogenesis, led to systemic induction of interleukin (IL) 1, and profoundly exacerbated (50-90%) ischemic brain injury in rats and mice, a response that was more severe in combination with old age and atherosclerosis. Systemic blockade of IL-1 with IL-1 receptor antagonist (IL-1Ra) fully reversed infection-induced exacerbation of brain injury and functional impairment caused by cerebral ischemia. We show that infection-induced systemic inflammation mediates its effects via increasing platelet activation and microvascular coagulation in the brain after cerebral ischemia, as confirmed by reduced brain injury in response to blockade of platelet glycoprotein (GP) Ibα. IL-1 and platelet-mediated signals converge on microglia, as both IL-1Ra and GPIbα blockade reversed the production of IL-1α by microglia in response to cerebral ischemia in infected animals. INTERPRETATION: S. pneumoniae infection augments atherosclerosis and exacerbates ischemic brain injury via IL-1 and platelet-mediated systemic inflammation. These mechanisms may contribute to diverse cardio- and cerebrovascular pathologies in humans.

Surgical manipulation compromises leukocyte mobilization responses and inflammation after experimental cerebral ischemia in mice.

Acute brain injury results in peripheral inflammatory changes, although the impact of these processes on neuronal death and neuroinflammation is currently unclear. To facilitate the translation of experimental studies to clinical benefit, it is vital to characterize the mechanisms by which acute brain injury induces peripheral inflammatory changes, and how these are affected by surgical manipulation in experimental models. Here we show that in mice, even mild surgical manipulation of extracranial tissues induced marked granulocyte mobilization (300%) and systemic induction of cytokines. However, intracranial changes induced by craniotomy, or subsequent induction of focal cerebral ischemia were required to induce egress of CXCR2-positive granulocytes from the bone marrow. CXCR2 blockade resulted in reduced mobilization of granulocytes from the bone marrow, caused an unexpected increase in circulating granulocytes, but failed to affect brain injury induced by cerebral ischemia. We also demonstrate that isoflurane anaesthesia interferes with circulating leukocyte responses, which could contribute to the reported vascular and neuroprotective effects of isoflurane. In addition, no immunosuppression develops in the bone marrow after experimental stroke. Thus, experimental models of cerebral ischemia are compromised by surgery and anaesthesia in proportion to the severity of surgical intervention and overall tissue injury. Understanding the inherent confounding effects of surgical manipulation and development of new models of cerebral ischemia with minimal surgical intervention could facilitate better understanding of interactions between inflammation and brain injury.

Interleukin-1 mediates neuroinflammatory changes associated with diet-induced atherosclerosis.

BACKGROUND: Systemic inflammation contributes to brain pathology in cerebrovascular disease through mechanisms that are poorly understood. METHODS AND RESULTS: Here we show that atherosclerosis, a major systemic inflammatory disease, is associated with severe cerebrovascular inflammation in mice and that this effect is mediated by the proinflammatory cytokine interleukin-1 (IL-1). Apolipoprotein E-deficient mice fed Paigen or Western diets develop vascular inflammation, microglial activation, and leukocyte recruitment in the brain, which are absent in apolipoprotein E-deficient mice crossed with IL-1 type 1 receptor-deficient mice. Systemic neutralization of IL-1ß with an anti-IL-1ß antibody reversed aortic plaque formation (by 34% after a Paigen and 45% after a Western diet) and reduced inflammatory cytokine expression in peripheral organs. Central, lipid accumulation-associated leukocyte infiltration into the choroid plexus was reversed by IL-1ß antibody administration. Animals fed a Western diet showed 57% lower vascular inflammation in the brain than that of mice fed a Paigen diet, and this was reduced further by 24% after IL-1ß antibody administration. CONCLUSIONS: These results indicate that IL-1 is a key driver of systemically mediated cerebrovascular inflammation and that interventions against IL-1ß could be therapeutically useful in atherosclerosis, dementia, or stroke. (J Am Heart Assoc. 2012;1:e002006 doi: 10.1161/JAHA.112.002006.).

Delayed administration of interleukin-1 receptor antagonist reduces ischemic brain damage and inflammation in comorbid rats.

Many neuroprotective agents have been effective in experimental stroke, yet few have translated into clinical application. One reason for this may be failure to consider clinical comorbidities/risk factors in experimental models. We have shown that a naturally occurring interleukin-1 receptor antagonist (IL-1Ra) is protective against ischemic brain damage in healthy animals. However, protective effects of IL-1Ra have not been determined in comorbid animals. Thus, we tested whether IL-1Ra protects against brain injury induced by experimental ischemia in aged JCR-LA (corpulent) rats, which have clinically relevant risk factors. Male, aged, lean, and corpulent rats exposed to transient (90 minutes) occlusion of the middle cerebral artery (tMCAO) were administered two doses of IL-1Ra (25 mg/kg, subcutaneously) during reperfusion. Brain injury and neuroinflammatory changes were assessed 24 hours after tMCAO. Our results show that IL-1Ra administered at reperfusion significantly reduced infarct volume measured by magnetic resonance imaging (50%, primary outcome) and blood-brain barrier disruption in these comorbid animals. Interleukin-1Ra also reduced microglial activation, neutrophil infiltration, and cytokines levels in the brain. These data are the first to indicate that IL-1Ra protects against ischemic brain injury when administered via a clinically relevant route and time window in animals with multiple risk factors for stroke.

Brain inflammation is induced by co-morbidities and risk factors for stroke.

Chronic systemic inflammatory conditions, such as atherosclerosis, diabetes and obesity are associated with increased risk of stroke, which suggests that systemic inflammation may contribute to the development of stroke in humans. The hypothesis that systemic inflammation may induce brain pathology can be tested in animals, and this was the key objective of the present study. First, we assessed inflammatory changes in the brain in rodent models of chronic, systemic inflammation. PET imaging revealed increased microglia activation in the brain of JCR-LA (corpulent) rats, which develop atherosclerosis and obesity, compared to the control lean strain. Immunostaining against Iba1 confirmed reactive microgliosis in these animals. An atherogenic diet in apolipoprotein E knock-out (ApoE(-/-)) mice induced microglial activation in the brain parenchyma within 8 weeks and increased expression of vascular adhesion molecules. Focal lipid deposition and neuroinflammation in periventricular and cortical areas and profound recruitment of activated myeloid phagocytes, T cells and granulocytes into the choroid plexus were also observed. In a small, preliminary study, patients at risk of stroke (multiple risk factors for stroke, with chronically elevated C-reactive protein, but negative MRI for brain pathology) exhibited increased inflammation in the brain, as indicated by PET imaging. These findings show that brain inflammation occurs in animals, and tentatively in humans, harbouring risk factors for stroke associated with elevated systemic inflammation. Thus a "primed" inflammatory environment in the brain may exist in individuals at risk of stroke and this can be adequately recapitulated in appropriate co-morbid animal models.