Inflammation after Stroke: A Local Rather Than Systemic Response?

0 downloads 0 Views 894KB Size Report
straints on cerebellar granule cell combinatorial diversity. J. Neurosci. 37, 12153–12166. Spotlight. Inflammation after. Stroke: A Local Rather. Than Systemic.
TINS 1469 No. of Pages 3

Spotlight

Inflammation after Stroke: A Local Rather Than Systemic Response? Ruslan Rust ,1,2,4,* Lisa Grönnert,3,4 and Martin E. Schwab1,2 After injury, activation and recruitment of inflammatory and immune cells has been thought to occur throughout the whole body. A recent study shows that after brain injury in mice, immune cells are primarily recruited from nearby skull bone marrow and invade the brain through microscopic vascular channels. Manipulation of this process may provide new therapeutic options. Inflammation is known to play a dual role in the pathogenesis and outcome of CNS injuries, having both beneficial and detrimental effects [1]. After stroke, damaged brain tissue elicits a systemic inflammatory response that involves the recruitment of immune cells. This response is mediated, at least in part, by activating the bone marrow via the sympathetic nervous system. Neutrophils are among the first immune cells accumulating in the ischemic brain, within minutes after the injury [2]. Although there is detailed knowledge about the overall process of activation and recruitment, the proportional contribution of cells from different bone marrow compartments is unclear. Until now, it has been generally assumed that inflammatory stimuli trigger the activation and release of immune cells into the systemic circulation from all over the body, followed by their infiltration into the injury site [3].

In a recent study, Herisson and colleagues [4] challenge this view and suggest that after stroke, immune cells preferentially arise from local skull bone marrow through microscopic vascular channels (Figure 1). To visualize this pathway, the team developed a strategy to differentially label bone marrow cells residing in the mouse skull and tibia, the large shinbone, with different fluorescent membrane dyes. This site-specific labeling allowed the tracking and determination of the origin of the cells after recruitment to the injury site. In particular, the authors injected red and green dyes into the skull and tibia, respectively, and isolated the destination tissues in several models of acute inflammation, including ischemic forebrain cortical stroke, acute myocardial infarction, and aseptic meningoencephalitis. The contribution of immune cells from the skull and tibia to the injury sites was subsequently assessed by flow cytometry. This revealed that ischemic stroke and aseptic meningoencephalitis elicited a higher contribution of skull neutrophils to brain inflammation than tibial neutrophils, along with a significant decrease of immune cells in the skull bone marrow compartment. By contrast, neutrophil contributions to myocardial inflammation were comparable between the skull and the tibia. To decipher the underlying mechanisms of this disparity, the researchers compared levels of the leukocyte retention factor SDF-1 and vascular permeability in the bone marrow that may regulate leukocyte release into the circulation. A decrease of SDF-1, a chemokine that retains leukocytes in hematopoietic niches, was observed only in the skull after cortical stroke. A trend toward higher vascular permeability was detectable in the skull marrow after aseptic meningoencephalitis, indicating that both factors may contribute to the

preferred mobilization of skull neutrophils to brain inflammation. Herisson and colleagues then hypothesized that this recruitment bias could be due to the close anatomic proximity of the skull marrow to the brain and assumed the presence of direct vascular connections as a route for migrating immune cells and/or inflammatory mediators. To investigate this, they inspected the skull–brain interface using confocal microscopy, and notably discovered vascular channels that connect the skull marrow with the subdural vasculature of the brain surface. The blood flow in these channels was directed toward the skull marrow. However, surprisingly, in vivo time-lapse imaging identified neutrophils traveling against the flow. After stroke or aseptic meningoencephalitis, neutrophils exited the channels more frequently into the inflamed brain parenchyma. The presence of such channels was also confirmed in human skull tissue by imaging craniectomy specimens. However, their function remains to be elucidated. Overall, the study by Herisson and colleagues points to a direct local interaction between the brain, especially after damage, and neutrophils residing in the skull bone marrow. This is of particular interest since neutrophils are among the first immune cells to respond after cerebral ischemia, and beside their adaptive roles, their actions can also have dominant detrimental effects. Specifically, their invasion into the ischemic tissue is directly associated with blood–brain barrier disruption, edema, neuronal death, infarct severity, and worse neurological outcomes [5]. On activation and infiltration into the injury site, neutrophils produce various reactive oxygen species (ROS), which contribute to tissue damage after injury. Moreover, neutrophils exert antibacterial properties by releasing lytic substances, which simultaneously promote

Trends in Neurosciences, Month Year, Vol. xx, No. yy

1

TINS 1469 No. of Pages 3

Tradional view

New mechanism Addional direct route through vascular channels

Ischemic stroke induces systemic immune response in enre hematopoiec system

Systemically circulang immune cells are uniformly recruited to site of injury

Immune cells are preferenally acvated and recruited from skull bone marrow through microvascular channels

Figure 1. Activation and Recruitment of Neutrophils after Stroke. According to the traditional view (left), ischemic stroke induces a systemic immune response in the entire hematopoietic system. This leads to activation and recruitment of immune cells such as neutrophils through the circulation to the injury site (left). Herisson et al. [4] propose an additional, complementary mechanism (right) involving a direct route of recruitment through vascular channels in the skull. Neutrophils that originate from the skull marrow are preferentially recruited to the cortical injury site after stroke.

extracellular matrix breakdown and vas- blockage of neutrophil recruitment led to studies to clarify the channels’ function, cular damage [6]. an increased rate of infections including including in humans, under physiological meningitis that were associated with and pathological conditions. Due to these detrimental effects, neutro- worse stroke outcomes [9]. 1 Institute for Regenerative Medicine, University of Zurich, phils have been recognized as a treatZurich, Switzerland ment target to reduce brain injury after The study by Herisson et al. may reveal a 2 Department of Health Sciences and Technology, ETH stroke. In experimental cerebral ischemia, new therapeutic strategy in which a sub- Zurich, Zurich, Switzerland a variety of therapeutic interventions set of neutrophils is targeted locally rather 3DFG Center for Regenerative Therapies Dresden/TU 01307 Dresden, Germany reducing the neutrophil response suc- than relying on nonselective neutrophil Dresden, 4 These authors contributed equally to this work cessfully reduced lesion size in rodents blockage. In particular, the local, specific [7,8]. In particular, targeting of neutrophil inhibition of skull-derived inflammatory *Correspondence: [email protected] (R. Rust). activation and recruitment, as well as cells migrating through the newly https://doi.org/10.1016/j.tins.2018.09.011 release of proteases, has been proposed described vascular channels may avoid References as a neuroprotective therapy for stroke. the side effects of systemic immune sup- 1. Iadecola, C. and Anrather, J. (2011) The immunology of stroke: from mechanisms to translation. Nat. Med. 17, 796–808 Until now, however, these results could pression after stroke. The harnessing of 2. Jickling, G.C. et al. (2015) Targeting neutrophils in ischemic not be confirmed in human stroke these channels for therapeutic purposes, stroke: translational insights from experimental studies. patients. In a clinical study, the systemic however, will first require additional J. Cereb. Blood Flow Metab. 35, 888–901 2

Trends in Neurosciences, Month Year, Vol. xx, No. yy

TINS 1469 No. of Pages 3

3. Courties, G. et al. (2015) Ischemic stroke activates hematopoietic bone marrow stem cells. Circ. Res. 116, 407–417 4. Herisson, F. et al. (2018) Direct vascular channels connect skull bone marrow and the brain surface enabling myeloid cell migration. Nat. Neurosci. 21, 1209–1217 5. Ruhnau, J. et al. (2017) Thrombosis, neuroinflammation, and poststroke infection: the multifaceted role of neutrophils in stroke. J. Immunol. Res. 2017, 5140679

6. Stowe, A.M. et al. (2009) Neutrophil elastase and neurovascular injury following focal stroke and reperfusion. Neurobiol. Dis. 35, 82–90

8. Gelderblom, M. et al. (2012) Neutralization of the IL-17 axis diminishes neutrophil invasion and protects from ischemic stroke. Blood 120, 3793–3802

7. Herz, J. et al. (2015) Role of neutrophils in exacerbation of brain injury after focal cerebral ischemia in hyperlipidemic mice. Stroke 46, 2916–2925

9. Enlimomab Acute Stroke Trial Investigators (2001) Use of anti-ICAM-1 therapy in ischemic stroke: results of the Enlimomab Acute Stroke Trial. Neurology 57, 1428–1434

Trends in Neurosciences, Month Year, Vol. xx, No. yy

3