Abstract
The lectin pathway (LP) of complement activation is believed to contribute to brain inflammation. The study aims to identify the key components of the LP contributing to TBI outcome as possible novel pharmacological targets. We compared the long-term neurological deficits and neuropathology of wild-type mice (WT) to that of mice carrying gene deletions of key LP components after experimental TBI. WT or MASP-2 (Masp2−/−), ficolin-A (Fcna−/−), CL-11 (Colec11−/−), MASP-1/3 (Masp1−/−), MBL-C (Mbl2−/−), MBL-A (Mbl1−/−) or MBL−/− (Mbl1−/−/Mbl2−/−) deficient male C57BL/6J mice were used. Mice underwent sham surgery or TBI by controlled cortical impact. The sensorimotor response was evaluated by neuroscore and beam walk tests weekly for 4 weeks. To obtain a comparative analysis of the functional outcome each transgenic line was rated according to a health score calculated on sensorimotor performance. For selected genotypes, brains were harvested 6 weeks after injury for histopathological analysis. MASP-2−/−, MBL−/− and FCN-A−/− mice had better outcome scores compared to WT. Of these, MASP-2−/− mice had the best recovery after TBI, showing reduced sensorimotor deficits (by 33% at 3 weeks and by 36% at 4 weeks). They also showed higher neuronal density in the lesioned cortex with a 31.5% increase compared to WT. Measurement of LP functional activity in plasma from MASP-2−/− mice revealed the absence of LP functional activity using a C4b deposition assay. The LP critically contributes to the post-traumatic inflammatory pathology following TBI with the highest degree of protection achieved through the absence of the LP key enzyme MASP-2, underlining a therapeutic utility of MASP-2 targeting in TBI.
Highlights
Traumatic brain injury (TBI) is associated with a primary biomechanical injury that can involve contusion and laceration, diffuse axonal injury, brain swelling and intracranial haemorrhage [1,2,3] followed by a secondary injury, which is caused by the activation of several molecular andThe complement system, an important component of the innate and adaptive immune response, is a major coordinator of post-traumatic neuroinflammation and secondary neuropathology after TBI [10,11,12,13,14]
We found that MASP-2−/−, MBL−/− and FCN-A−/− mice had lower neurological deficits after TBI, indicating that these lectin pathway (LP) components are actively involved in driving the traumatic lesion and identifies them as possible pharmacological targets to reduce post-traumatic loss of functional activity and to improve recovery and clinical outcome
The data is shown as a scatter dot plot, line at mean ± SEM (n = 6); Two-way Anova followed by Sidak’s post hoc test. d Representative high-magnification images of CD11b positive cells showing activated microglia in the ipsilateral side of both wild-type mice (WT) and MASP-2−/− TBI mice, scale bar 20 μm MASP-2 should be a more effective target than one of the five LP initiators
Summary
Traumatic brain injury (TBI) is associated with a primary biomechanical injury that can involve contusion and laceration, diffuse axonal injury, brain swelling and intracranial haemorrhage [1,2,3] followed by a secondary injury, which is caused by the activation of several molecular andThe complement system, an important component of the innate and adaptive immune response, is a major coordinator of post-traumatic neuroinflammation and secondary neuropathology after TBI [10,11,12,13,14]. Carbohydrate structures or acetylated proteins exposed on the surface of damaged cells, including apoptotic or necrotic cells and stressed endothelium [16], are typical DAMPs recognized by the LP. Recognition of these signals by initiator molecules leads to activation of the associated serine proteases MASPs (MBL-associated serine proteases) and subsequent activation of the complement cascade. In addition to its role as an LP initiator, the recognition subcomponent MBL was shown to possess direct activity, driving platelet-dependent inflammation and vascular damage following ischemic injury [16, 20]. TBI shares blood perfusion deficits and metabolic derangements with ischemic injury [21], suggesting that similar mechanisms might be involved in the traumatic pericore tissue [22], an area subjected to post-injury hypoxia [23]
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