Mannose-Binding Lectin Drives Platelet Inflammatory Phenotype and Vascular Damage After Cerebral Ischemia in Mice via IL (Interleukin)-1α

Orsini, Franca; Fumagalli, Stefano; Császár, Eszter; Tóth, Krisztina; Blasio, Daiana De; Zangari, Rosalia; Lénárt, Nikolett; Simoni, Maria Grazia De

doi:10.1161/atvbaha.118.311058

Cited by 35 publications

(44 citation statements)

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“…In particular, MBL itself has been shown to promote vascular injury on endothelial cells having undergone hypoxic stimulus by direct action -including structural damage to the endothelial cell cytoskeletonwithout requiring LP activation 16 . Consistent with this finding, genetic deletion of MBL or its pharmacological inhibition were sufficient to obtain significant protection in experimental models of ischemic stroke, where vascular dysfunction is critical 21,24,39 . The fact that in experimental TBI, MBL depletion provided a lower degree of protection than MASP-2 depletion may suggest that MBL complement-independent vascular effects are less important for TBI pathophysiology.…”

Section: Discussionsupporting

confidence: 63%

“…Genetic deletion of LP sub-components (MBL or MASP-2) [21][22][23] or their pharmacological targeting 21,22 are protective in experimental models of brain ischemia. In addition to a key role of the enzyme MASP-2, the recognition subcomponent MBL itself was shown to possess direct activity, driving platelet-dependent inflammation and vascular damage following ischemic injury independent of LP activation 16,24 . Of note, TBI shares blood perfusion deficits and metabolic derangements with ischemic injury 25 , thus suggesting that similar mechanisms might be involved in the traumatic pericore tissue, an area subjected to post-injury hypoxia 26 .…”

Section: Introductionmentioning

confidence: 99%

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Targeted deletions of complement lectin pathway genes improve outcome in traumatic brain injury

Mercurio

Oggioni

Fumagalli

et al. 2020

Preprint

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The complement system is believed to contribute to inflammation in acute brain injury. This work defines the neurobehavioral response to traumatic brain injury (TBI) modeled by controlled cortical impact in wild-type mice and in mice carrying gene-targeted deficiencies of individual components of the lectin pathway of complement activation to identify the key components contributing to pathology. Targeted gene deletions include: the recognition subcomponents ficolin-A, CL-11, MBL-C and MBL-A, both individually and combined, and the serine proteases MASP-1, MASP-2 and MASP-3. Our results demonstrate that MASP-2 deficiency brings the highest protective phenotype, countering long-term neuroinflammatory injury following TBI, as shown by reduced neuronal deficits and neuronal cell loss compared to wild-type mice. This study highlights MASP-2 as a promising pharmacological target in patients suffering from TBI, a leading cause of death and disability.

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Section: Discussionsupporting

confidence: 63%

Section: Introductionmentioning

confidence: 99%

Targeted deletions of complement lectin pathway genes improve outcome in traumatic brain injury

Mercurio

Oggioni

Fumagalli

et al. 2020

Preprint

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“…Current evidence indicates that MBL can activate multiple mechanisms of brain vascular damage that contribute to ischemic injury independent of complement system activation. 3,12 In addition to MBL-A's greater ability to activate the complement system than MBL-C, a further explanation for MBL-A's contribution to ischemic injury may be that it is activated earlier after ischemia than MBL-C. The gene encoding MBL-A (Mbl1) was overexpressed 24 h after ischemia, preceding the overexpression of the gene encoding MBL-C (Mbl2, 48 h).…”

Section: Discussionmentioning

confidence: 99%

“…It is likely that targeting MBL-A results in a stronger protective effect than targeting MBL-C owing to the role of MBL-A in the initial phases after ischemia, when it starts detrimental cascades that are hard to counteract at later stages. These cascades include-along with complement activationinflammatory platelet activation, 12 prothrombotic pathways, 11 and immune cell activation. 20 Whether the activation of specific cascades is linked to each MBL isoform remains to be clarified; however, the fact that depletion of both MBL isoforms results in the highest degree of protection supports the hypothesis that both isoforms play a role in ischemic brain injury, most likely activating different routes of damage.…”

Section: Discussionmentioning

confidence: 99%

“…3 New evidence indicates that MBL, in addition to activating the LP, activates prothrombotic cascades via its associated serine proteases [9][10][11] and directly activates an inflammatory phenotype in platelets. 12 Thus, MBL offers a promising therapeutic target for brain ischemia-it is systemically accessible and controls many mechanisms of injury. Our group previously demonstrated that pharmacological targeting of MBL by intravenous injection of an anti-MBL antibody or Polyman2, a mannosylated molecule acting as an MBL inhibitor, 2,13 improves neurological deficits and reduces the severity of cerebral lesions in ischemic rats and mice.…”

Section: Introductionmentioning

confidence: 99%

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Specific contribution of mannose-binding lectin murine isoforms to brain ischemia/reperfusion injury

et al. 2019

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Mannose-binding lectin (MBL), an initiator of the lectin pathway (LP) of complement activation, is detrimental in ischemic stroke, as shown in clinical studies and rodent models. Whereas humans have one functional MBL protein, rodents have two isoforms, MBL-A and MBL-C, whose functions relative to that of human MBL are unknown. To permit the clinical translation of preclinical data, we aimed to define the specific contributions of MBL-A and MBL-C to brain ischemia. We subjected mice with double (MBL −/−) or single (MBL-A −/− or MBL-C −/−) MBL isoform depletion to transient middle cerebral artery occlusion (tMCAo). MBL −/− mice had fewer neurological deficits and smaller ischemic lesions than WT mice. MBL-A −/− mice had smaller lesions than WT mice and exhibited no significant behavioral defects, whereas MBL-C −/− mice did not differ from WT mice. The induction of Mbl1 and Mbl2 (the MBL-A and MBL-C genes) expression 48 h after tMCAo was similar across genotypes. The time course of Mbl1 and Mbl2 expression in WT ischemic mice showed that Mbl1 activation occurred earlier (24 h) than Mbl2 activation (48 h). The plasma levels of MBL-A and MBL-C in MBL-C −/− and MBL-A −/− mice, respectively, were similar to those in WT mice both at baseline and at 48 h after tMCAo. At 48 h, MBL-A −/− ischemic mice showed higher MBL-C levels in the brain than WT mice. WT and MBL-C −/− ischemic mice had higher LP activity in plasma and, accordingly, higher levels of C3 deposition in the brain than MBL-A −/− and MBL −/− mice. In conclusion, mice with depletion of both MBL isoforms exhibited strong protection from ischemia/reperfusion injury. MBL-A was the main contributor to injury, likely owing to its earlier activation after ischemia and more efficient activation of the complement system than MBL-C.

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Microglia–neuron–vascular interactions in ischemia

Lénárt,

Cserép,

Császár

et al. 2023

Glia

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Cerebral ischemia is a devastating condition that results in impaired blood flow in the brain leading to acute brain injury. As the most common form of stroke, occlusion of cerebral arteries leads to a characteristic sequence of pathophysiological changes in the brain tissue. The mechanisms involved, and comorbidities that determine outcome after an ischemic event appear to be highly heterogeneous. On their own, the processes leading to neuronal injury in the absence of sufficient blood supply to meet the metabolic demand of the cells are complex and manifest at different temporal and spatial scales. While the contribution of non‐neuronal cells to stroke pathophysiology is increasingly recognized, recent data show that microglia, the main immune cells of the central nervous system parenchyma, play previously unrecognized roles in basic physiological processes beyond their inflammatory functions, which markedly change during ischemic conditions. In this review, we aim to discuss some of the known microglia–neuron–vascular interactions assumed to contribute to the acute and delayed pathologies after cerebral ischemia. Because the mechanisms of neuronal injury have been extensively discussed in several excellent previous reviews, here we focus on some recently explored pathways that may directly or indirectly shape neuronal injury through microglia‐related actions. These discoveries suggest that modulating gliovascular processes in different forms of stroke and other neurological disorders might have presently unexplored therapeutic potential in combination with neuroprotective and flow restoration strategies.

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Mannose-Binding Lectin Drives Platelet Inflammatory Phenotype and Vascular Damage After Cerebral Ischemia in Mice via IL (Interleukin)-1α

Abstract: Supplemental Digital Content is available in the text.

Cited by 35 publications

References 58 publications

Targeted deletions of complement lectin pathway genes improve outcome in traumatic brain injury

Targeted deletions of complement lectin pathway genes improve outcome in traumatic brain injury

Specific contribution of mannose-binding lectin murine isoforms to brain ischemia/reperfusion injury

Microglia–neuron–vascular interactions in ischemia

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