Dickkopf-1 release by the bone marrow upon ischemic stroke bridges neurovascular and immune deregulations

Abstract

Neurovascular and immune alterations decisively govern definitive damage maturation after stroke. Dickkopf (DKK)1 elevated levels in the blood circulation of stroke patients correlate with poor outcomes. Herein, we report that Dkk1 mRNA expression is not endogenously present in the healthy brain, and is barely and sparsely detectable at the lesion site in experimental ischemic stroke. Notably, we reveal a progressive increased protein expression of peripheral DKK1 in the subacute phase. Using genetic tools and bone marrow replacement approaches to mediate conditional DKK1 tissue-specific induction in conjunction with imaging, molecular, transcriptomic and functional studies, we demonstrate that DKK1 high levels at stroke onset accelerate subacute injury progression via deregulation of neurovascular functions. DKK1 prolonged post-stroke elevated levels mediate a chronic neuroinflammation associated with anxiety-like behaviors. DKK1 restricted induction in the bone marrow is sufficient to accelerate the subacute damage progression. DKK1 modulates the subacute peripheral immune response, suggesting that its de novo bone marrow expression represents a novel mechanism to regulate hematopoiesis in response to stroke. Neutralization of DKK1’s biological activity improves stroke outcomes. Our results indicate that DKK1 bone marrow release is a major determinant of definitive damage maturation after stroke and that its neutralization constitutes a promising disease-modifying therapeutic avenue.