Iadecola and Anrather reply:
We thank Osthoff and his colleagues1 for their interest in our review2 and for highlighting their interesting work on mannose-binding lectin (MBL) deficiency. Our review focused primarily on the role of innate and adaptive immunity in ischemic brain injury, aiming to develop a conceptual framework in which to place the rapidly expanding preclinical data on this topic. Our intent was not to provide an exhaustive list of all the potential anti-inflammatory therapies for ischemic stroke—and there are many—but to broadly highlight the therapeutic opportunities afforded by modulation of innate and adaptive immunity. Accordingly, we stressed the importance of complement in the early stages of cerebral ischemia in the text and featured it in Table 3 as a valuable target for developing new treatments for ischemic stroke2. Modulation of MBL is certainly a potential therapeutic strategy to suppress the deleterious effects of complement activation in the setting of cerebral ischemia. However, the limited preclinical and clinical data on the role of MBL in acute brain injury3,4,5,6 call for caution and additional scrutiny. Of the two studies that directly assessed the role of MBL in transient middle cerebral artery occlusion in MBL-deficient mice, one showed a sizable reduction in cortical and subcortical injury volume3, whereas the other showed a modest reduction only subcortically5. Furthermore, in contrast, a worsening of the outcome was observed in another study on traumatic brain injury6.
As for clinical studies, the association between MBL deficiency and improved stroke outcome is consistent with a beneficial effect3,4, but larger sample sizes and greater mechanistic insights are needed to guide clinical intervention. For example, the effects of MBL deficiency on thromboembolic diseases, including stroke, are not unequivocally beneficial7,8,9,10. Indeed, the link between complement and brain injury is complex. Some complement subunits (C3a and C5a) are neuroprotective by counteracting excitoxicity and promoting neurogenesis11. Furthermore, inhibition of complement has not been consistently associated with an improved outcome in cerebral ischemia12,13,14,15. In contrast, in patients with acute myocardial infarction the C5 complement–specific antibody pexelizumab showed a tendency to reduce stroke, an effect that was not statistically significant but was promising16. Therefore, the complement system, including the MBL pathway17, remains an attractive therapeutic target, and we look forward to further basic and clinical developments in this promising area of stroke research.
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The authors declare no competing financial interests.
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Iadecola, C., Anrather, J. Reply to: Mannose-binding lectin—the forgotten molecule?. Nat Med 17, 1548 (2011). https://doi.org/10.1038/nm.2589