Platelet interleukin-1α drives cerebrovascular inflammation

Abstract

IntroductionCerebrovascular inflammation is a major contributor to diverse forms of brain injury, including cerebral ischemia, multiple sclerosis, cerebral infection, and epilepsy. 1-3 Peripheral circulating cells play critical roles in cerebral inflammation. Platelets are one of the first cell types to arrive at the site of vascular dysfunction 4 and can induce vascular inflammation, thus contributing to disease progression, particularly in larger vessels.The effects of platelets on microvascular endothelial cells are poorly understood, although interactions between these cellular entities are documented in the brain in response to cerebral ischemia in several species 5-9 and in cerebral malaria in humans. 10 Platelet activation occurs in response to stroke in humans 11,12 and in patients with multiple sclerosis. 13 Platelet consumption or brain accumulation 14 in the infarct area may account for the drop in platelet numbers after clinical stroke. 15 Inhibition of platelet adhesion to brain endothelium may protect against diverse brain insults. Neutralizing platelet glycoprotein (GP) VI or GPIb surface adhesion receptors reduces damage in mouse focal cerebral ischemia. 16 Inhibition of platelet-brain endothelial interactions, through blockade of platelet GPIIb receptor, protects mice against cerebral malaria pathogenesis. 17 Mice lacking platelet GPIIb 18 or mice receiving a small molecule inhibitor of GPIIb/IIIa (CD41/CD61) are also protected against cerebral ischemia. 5 However, the mechanisms by which platelets contribute to brain injury are unknown.Current therapies for the treatment of acute cerebral ischemia target platelet function, with protective effects dependent on anticoagulant or fibrinolytic actions. However, inhibition of coagulatory pathways reduces inflammation. 19 Thus, the antiinflammatory effects of platelet inhibition may mediate some of the protection afforded by these therapies in cerebral ischemia. Platelet interleukin-1␣ (IL-1␣), IL-1␤, or CD40L can activate peripheral endothelial cells, [20][21][22][23][24] and platelets contribute to leukocyte infiltration in peripheral tissues. 25,26 Similar mechanisms may contribute to brain endothelial activation.Here, we tested the hypothesis that platelets induce inflammatory activation of brain endothelial cells. We show, for the first time, that platelet-secreted IL-1␣ drives mouse brain endothelial activation, leading to the induction of endothelial ICAM-1 and VCAM-1, CXCL1 release, and neutrophil transendothelial migration (TEM). This study is the first to show that actions of platelet IL-1␣ on brain endothelium may be critical to inflammationmediated injury in the brain. MethodsMore details regarding the procedures outlined herein are given in supplemental Methods (available on the Blood Web site; see the Supplemental Materials link at the top of the online article). Focal cerebral ischemia and immunohistochemistryFocal cerebral ischemia in C57/BL6 or IL-1␣/␤ Ϫ/Ϫ mice (on a C57/BL6 background 27 ) induced by transient (60 minutes) middle cer...

IL-1α and IL-1β Recruit Different Myeloid Cells and Promote Different Stages of Sterile Inflammation

“…Whereas most studies focused on the biological activity of mature IL-1a in inflammation, some reports also described activities of the precursor molecule. For example, in a mouse model of cerebrovascular inflammation, the precursor of IL-1a in platelets was shown to mediate infiltration of neutrophils (43), the effects of vitamin D on upregulation of the IL-1a precursor in skin keratinocytes (30), as well as the role of precursor IL-1a in collagen deposition in systemic sclerosis in fibroblasts (44). The exact pathway(s) of signaling of the different IL-1 molecules through IL-1RI and its biological consequences is not completely clear, as no comparative studies with the different IL-1 molecules derived from cells have been performed.…”

Astrocytes Are Primed by Chronic Neurodegeneration to Produce Exaggerated Chemokine and Cell Infiltration Responses to Acute Stimulation with the Cytokines IL-1β and TNF-α

“…In the current study, this unexpected TNF-␣-induced CXCL1 production leads to robust neutrophil infiltration, indicating a weakening of regulation of extravasation in the diseased brain. Chemokine expression at the brain endothelium contributes to neutrophil recruitment (Thornton et al, 2010) and many neutrophils were recruited to the glia limitans in NBH ϩ IL-1␤ animals. However, very few of these extravasated into the tissue compared to ME7 ϩ IL-1␤, with most remaining at the glia limitans at 24 h (Fig.…”

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

“…We reported recently that platelet-derived IL-1a can induce cerebrovascular inflammation. 42 Activated platelets release IL-1 and/or IL-1-containing microparticles upon interacting with the endothelium. 42,43 We have demonstrated previously that peripheral IL-1 administration exacerbates brain injury, 30 and inflammatory mechanisms reportedly contribute to cerebral ischemia even in the absence of systemic inflammation.…”

“…42 Activated platelets release IL-1 and/or IL-1-containing microparticles upon interacting with the endothelium. 42,43 We have demonstrated previously that peripheral IL-1 administration exacerbates brain injury, 30 and inflammatory mechanisms reportedly contribute to cerebral ischemia even in the absence of systemic inflammation. 28,29 Both GPIba blockade and IL-1Ra have been shown to be protective in uninfected animals.…”