Mechanisms of neuroinflammation and inflammatory neurodegeneration in acute brain injury

Editorial

05 August 2015

Editorial: Mechanisms of neuroinflammation and inflammatory neurodegeneration in acute brain injury

Arthur Liesz

and

Christoph Kleinschnitz

4,021 views

6 citations

Editors

Arthur Liesz

Ludwig Maximilian University of Munich

Christoph Kleinschnitz

Julius Maximilian University of Würzburg

Impact

IL-1 signaling pathways. In response to a stimulus such as lipopolysaccharide (LPS) transcription of the gene encoding IL-1β is initiated. IL-1β is made as an inactive precursor protein and caspase-1 cleaves this pro-IL-1β to make the active IL-1β. A variety of factors can promote or inhibit the release of active IL-1β. Once released, IL-1β binds to IL-1RI alongside IL-1 receptor accessory protein (IL-1RAcP) and signal transduction is triggered, including co-localization of myeloid differentiation primary response protein 88 (MyD88), IL-1 receptor associated kinase (IRAK-1) and IRAK-2, recruitment of TNF receptor associated factor 6 (TRAF-6) and activation of nuclear factor kappa B (NFκB) from complex with IκB. Conversely IL-1 receptor type II (IL-1RII) does not induce signal transduction.

Review

06 February 2015

Interleukin-1 and acute brain injury

Katie N. Murray

, 1 more and

Stuart M. Allan

24,964 views

136 citations

Acute lesions trigger morphological and functional changes from resident microglia. The diagram summarizes the main microglia’s temporal (hours to months) and spatial (infarct core, peri-infarct area and unlesioned tissue) kinetics after an ischemic lesion (Ito et al., 2007; Perego et al., 2011, 2013; Hu et al., 2012; Morrison and Filosa, 2013; Patel et al., 2013; Taylor and Sansing, 2013). Infarct core (pink, upper panel) is surrounded by penumbra (orange, middle panel) in the acute phase, a peri-infarct region in the intermediate phases and turns into a scar (gray, with or without cavitation depending on the species) in the chronic phase. During acute phase (first 24 h), microglia are the first to respond to the lesion: unless they die immediately by the ischemic processes of the core, they are activated gaining an M2 functional polarization. In the peri-infarct region, microglia are activated but are initially not polarized (M0). In the following days, microglia are further activated in the peri-infarct area, proliferate, migrate to the core to repopulate the corresponding cells and some of them die. Depending on the ischemic severity and neuronal damage in the peri-infarct regions, microglia gradually acquire different, region-dependent, polarization states and eventually shift from M2 to M1 microglia as core expands to penumbra and neurons die. At this period, blood-borne monocytes (blue cells) and lymphocytes and neutrophils (not shown here) infiltrate mainly the peri-infarct regions. During the subchronic phase (weeks), the core is further cleared from debris (amoeboid microglia turn into foam cells or die) and microglia in the peri-infarct area possibly follow regionally different paths (resting, activation or death), under processes not well studied so far. Foam cells are present (coming from both resident and blood-macrophages), while the numbers of blood-borne cells gradually decline. In the chronic phase (months), there are indications of long-term microglial activation and presence of residual foam cells in the peri-infarct tissue, with unknown significance so far. Importantly enough, the unlesioned tissue is not well studied so far but probably holds populations of activated microglia that respond or facilitate local degenerative processes. For the simplicity of the figure, we have not included the secreted cytokines produced by the microglia, their changes in their receptors and the contribution of other immune cells. M0: non-polarized microglia, M1: pro-inflammatory or classically activated microglia, M2: anti-inflammatory or alternatively activated microglia (Patel et al., 2013), “?” indicate lack of detailed information.

Perspective

23 February 2015

Microglia in action: how aging and injury can change the brain’s guardians

Athanasios Lourbopoulos

, 1 more and

Farida Hellal

15,932 views

84 citations

$Soluble fractalkine (sFKN) is released into the extracellular space after injury and acts as a chemotactic factor for microglia. (A) P7 mice were treated with saline (control) or ethanol to induce neuronal apoptosis (apoptotic), and the brains were incubated in DMEM on ice for 2 h to isolate brain-conditioned media (BCM). 2 mg of protein were TCA precipitated, run on a gel, and probed with anti-fractalkine via western blot. sFKN and lysate from mixed neural cultures were used for comparison. We found fractalkine in BCM from apoptotic, but not control brain (a, arrowhead points to band of interest). (B–D) Transwell migration assays were performed to determine whether microglia transmigrate toward fractalkine. Microglia were isolated from mixed glial cultures via the shake-off method and added to the upper chamber of a transwell insert. Attractant of interest was added to the bottom of the transwell. After 3 h of migration, the cells that had migrated to the bottom surface of the transwell were fixed, stained with DAPI, and counted. (B) Microglia migrate toward 0.1 nM of sFKN. A fractalkine-neutralizingantibody (3.5 μg/mL) was pre-incubated with either 0.1 nM of sFKN or CXCL12 [indicated by (+)]. This antibody specifically blocked fractalkine-induced migration, as CXCL12-induced migration was not inhibited. (C,D) Microglia migrate toward apoptotic BCM in a fractalkine-dependent manner. P7 mice were treated with saline as a control or ethanol to induce neuronal apoptosis. Brains were then incubated in DMEM on ice for 2 h to isolate BCM from saline-treated control (CTL BCM) or apoptotic brain (Apo BCM). BCM was used as a chemoattractant in the lower chamber for transwell migration assays. (C) Microglia migrate toward apoptotic BCM but not control BCM. A fractalkine-neutralizing antibody (3.5 μg/mL) was pre-incubated with apoptotic BCM [indicated by (+)] to block fractalkine-dependent migration and this prevented migration toward the apoptotic BCM. (D) Migration toward BCM was quantified in CX3CR1 heterozygous (HET) versus KO microglia. CX3CR1 deficient microglia fail to migrate toward apoptotic BCM. (B–D) Data is from repeated experiments, each replicate represents microglia harvested from a different animal (n = 4–6). (B–C) One-way ANOVA, *p < 0.05; (D) Two-way ANOVA, *p < 0.05.$

Original Research

07 November 2014

Fractalkine is a “find-me” signal released by neurons undergoing ethanol-induced apoptosis

Jennifer D. Sokolowski

, 3 more and

James W. Mandell

7,095 views

72 citations

General Commentary

07 July 2015

Corrigendum: Versatility of the complement system in neuroinflammation, neurodegeneration, and brain homeostasis

Franca Orsini

, 3 more and

Maria-Grazia De Simoni

2,766 views

5 citations

The complement system: an overview. Classical pathway (CP): C1q, the CP initiator, recognizes and binds antigen-antibody complexes or specific molecules, including β-amyloid, C reactive protein (CRP), DNA and apoptotic bodies. After binding, the C1r and C1s proteases subsequently cleave C4 and C2 to generate C4a, C4b, C2a, C2b, permitting the formation of C4b2a (CP C3 convertase). This complex cleaves C3 into C3a, which, in turn, acts as potent anaphylatoxin, and C3b that binds to the complex forming the C4b2a3b protein block (CP C5 convertase). Lectin pathway (LP): MBL, ficolin-1, ficolin-2, ficolin-3 and collectin-11, the LP initiators, recognize and bind high-density arrays of mannose, fucose and N-acetylated sugars exposed by pathogens or by self-altered cells. After binding, the MBL-associated serine proteases (MASPs), MASP-1 and -2, associated in complex with the above recognition molecules (MBL/ficolins), cleave C4 and C2, thereby forming C3 convertase and C5 convertase in a similar manner to that of the CP (Ehrnthaller et al., 2011). The role of the third serine protease, called MASP-3, remains unclear (Kjaer et al., 2013). Alternative pathway (AP): the activation of the AP is driven by a spontaneous hydrolysis of circulating C3 (called tick-over process) to form C3(H2O). This molecule then associates factor B and factor D to form C3bBb (AP C3 convertase). Similar to the C3 convertase generated in the CP and LP, this complex splits C3 into C3a and C3b, with the latter creating a new C3 convertase (AP amplification loop, dotted line), and/or binding C3 convertase already present to create the C3bBb3b complex (AP C5 convertase). Extrinsic pathway: the recent characterization of this activation pathway suggests that it is driven by activated proteolytic enzymes, including thrombin, plasmin, kallikrein, factor XIIa. Thrombin possesses its own C5 convertase activity and, under undefined conditions, has been shown to have the capacity to directly cleave C5 to generate the correspondent active fragments (Huber-Lang et al., 2006). Recently, it has been shown that the coagulation serine proteases are likewise able to cleave C3 (Markiewski et al., 2007; Amara et al., 2010). Terminal pathway: CP, AP, LP and the extrinsic pathway all converge at C5 convertase formation, activating a common cascade through the cleavage of C5 into the anaphylatoxin C5a and the active C5b. Finally, (1) C3b fragment binds the targeted cell allowing the assembly of C6, C7, C8 and C9 in a pore called membrane attack complex (C5b-9 or MAC), that causes the direct lysis of the cell; (2) many fragments, such as C3b and C4b as well as C5b, work as opsonins triggering an overactivation of the phagocytic response; (3) altogether complement components are able to orchestrate an adaptative immune reaction by communicating with multiple immune cells (Ricklin and Lambris, 2007) through different receptors, leading to a robust local and systemic inflammatory response.

Review

07 November 2014

Versatility of the complement system in neuroinflammation, neurodegeneration and brain homeostasis

Franca Orsini

, 3 more and

Maria-Grazia De Simoni

The immune response after brain injury is highly complex and involves both local and systemic events at the cellular and molecular level. It is associated to a dramatic over-activation of enzyme systems, the expression of proinflammatory genes and the activation/recruitment of immune cells. The complement system represents a powerful component of the innate immunity and is highly involved in the inflammatory response. Complement components are synthesized predominantly by the liver and circulate in the bloodstream primed for activation. Moreover, brain cells can produce complement proteins and receptors. After acute brain injury, the rapid and uncontrolled activation of the complement leads to massive release of inflammatory anaphylatoxins, recruitment of cells to the injury site, phagocytosis and induction of blood brain barrier (BBB) damage. Brain endothelial cells are particularly susceptible to complement-mediated effects, since they are exposed to both circulating and locally synthesized complement proteins. Conversely, during neurodegenerative disorders, complement factors play distinct roles depending on the stage and degree of neuropathology. In addition to the deleterious role of the complement, increasing evidence suggest that it may also play a role in normal nervous system development (wiring the brain) and adulthood (either maintaining brain homeostasis or supporting regeneration after brain injury). This article represents a compendium of the current knowledge on the complement role in the brain, prompting a novel view that complement activation can result in either protective or detrimental effects in brain conditions that depend exquisitely on the nature, the timing and the degree of the stimuli that induce its activation. A deeper understanding of the acute, subacute and chronic consequences of complement activation is needed and may lead to new therapeutic strategies, including the ability of targeting selective step in the complement cascade.

15,773 views

181 citations

Sequential events leading to neutrophil infiltration. First, release from DAMPs from injured cells activates resident microglia via PPRs to release proinflammatory factors including TNF-α. Second, IL-23 activates γδ T cells to rapidly secrete IL-17 in the ischemic tissue. Third, neutrophil infiltration is initiated via IL-17 and TNF-α synergistically induced expression of CXCL-1 in astrocytes.

Mini Review

05 November 2014

γδ T cells as early sensors of tissue damage and mediators of secondary neurodegeneration

7,044 views

49 citations

Scheme of pathophysiological reactions of leukocytes and microglia after traumatic brain injury as demonstrated by in vivo experiments. Under physiological conditions (green background), leukocytes pass the cerebral microcirculation in undisturbed blood flow, while some of them occasionally role on the endothelium. Microglia have a ramified shape and continuously scan the brain parenchyma with their processes. Following TBI (red background), the intravascular leukocytes start rolling and adhering to the endothelium, mediated by selectins and integrins respectively. Finally, they migrate into the damaged tissue. Microglia become activated by brain trauma, extend their processes towards the site of injury, and finally migrate towards the injury, taking up an amoeboid shape.

Review

04 November 2014

Contributions of the immune system to the pathophysiology of traumatic brain injury – evidence by intravital microscopy

Susanne M. Schwarzmaier

and

Nikolaus Plesnila

6,250 views

33 citations

Raster plots of exemplary normal and atypical reverberating bursts of the network activity recorded in a neocortical/astrocyte/microglial co-culture grown on an multi-electrode array (MEA) dish in control (CON) and 6 h after application of 3 μg/ml lipopolysaccharide (LPS). Data in (A–D) were recorded in control and in LPS, respectively. Small vertical ticks on horizontal lines are timestamps of spikes elicited by identified neurons as indicated. (A) Raster plot of a normal burst recorded in control before adding LPS. Note the time scale bar of 2 s. (B) Raster plot of an atypical burst recorded 6 h after adding LPS. Note the time scale bar of 20 s. (C) Plot of 13 similar normal bursts recorded in control during a time window of 200 s. (D) Plot of two atypical bursts recorded in LPS during 200 s (the first is shown in Figure 1B). The timestamps in (C,D) had the same pattern as in (A,B), i.e., upper and lower ticks relate to identified excitatory and inhibitory cells, respectively.

Original Research

03 November 2014

Atypical “seizure-like” activity in cortical reverberating networks in vitro can be caused by LPS-induced inflammation: a multi-electrode array study from a hundred neurons

Francesca Gullo

, 5 more and

Enzo Wanke

6,331 views

23 citations

Review

03 November 2014

Role of the kallikrein–kinin system in traumatic brain injury

Christiane Albert-Weissenberger

, 3 more and

Anna-Leena Sirén

6,178 views

25 citations

Perspective

21 October 2014

Nanobodies as modulators of inflammation: potential applications for acute brain injury

Björn Rissiek

, 1 more and

Tim Magnus

11,469 views

40 citations

General Commentary

17 October 2014

Commentary: Different immunological mechanisms govern protection from experimental stroke in young and older mice with recombinant TCR ligand therapy

Keith R. Pennypacker

2,165 views

1 citations

Mechanisms of post-ischemic inflammation. DAMPs are released into extracellular compartment and activate infiltrating immune cells by two ways: Signal 1 (via the activation of pattern recognition receptor) and Signal 2 (via the activation of inflammasome). Various inflammatory cytokines promote neuronal injury, and induce further inflammation mediated by T cells in subacute phase. After days and week after stroke onset, the resolution of post-ischemic inflammation is brought by the clearance of debris including DAMPs or inflammatory mediators, and the production of anti-inflammatory molecules or neurotrophic factors. In this recover phase, inflammatory immune cells turn into neuroprotective cells.

Review

14 October 2014

Post-ischemic inflammation regulates neural damage and protection

Takashi Shichita

, 1 more and

Akihiko Yoshimura

Post-ischemic inflammation is important in ischemic stroke pathology. However, details of the inflammation process, its resolution after stroke and its effect on pathology and neural damage have not been clarified. Brain swelling, which is often fatal in ischemic stroke patients, occurs at an early stage of stroke due to endothelial cell injury and severe inflammation by infiltrated mononuclear cells including macrophages, neutrophils, and lymphocytes. At early stage of inflammation, macrophages are activated by molecules released from necrotic cells [danger-associated molecular patterns (DAMPs)], and inflammatory cytokines and mediators that increase ischemic brain damage by disruption of the blood–brain barrier are released. After post-ischemic inflammation, macrophages function as scavengers of necrotic cell and brain tissue debris. Such macrophages are also involved in tissue repair and neural cell regeneration by producing tropic factors. The mechanisms of inflammation resolution and conversion of inflammation to neuroprotection are largely unknown. In this review, we summarize information accumulated recently about DAMP-induced inflammation and the neuroprotective effects of inflammatory cells, and discuss next generation strategies to treat ischemic stroke.

13,829 views

156 citations