FIGURE 4.

Central and peripheral immune response crosstalk in stroke. After ischemia, necrotic neuronal cells appear and release DAMPs due to intracellular adenosine triphosphate depletion and hypotonic hypoxia. On the one hand, DAMPs activate innate immune receptors on brain resident immune cells, leading to the release of cytokines and chemokines, which, in turn, promote additional neutrophil entry. Neutrophils damage the brain by producing reactive oxygen species and TNF. On the other hand, brain-derived DAMPs leak into the circulation and activate systemic immunity, mobilizing innate immune cells in lymphoid organs, the lungs, and the gut. Circulating peripheral immune cells subsequently extravasate into the brain parenchyma and meninges. In addition, the increase in gut permeability triggers bacteria and their metabolites to enter into the brain parenchyma. In the left part: Purple: Lung–Brain axis. Yellow: Lymphoid organs / bone marrow–Brain axis. Purple: Gut–Brain axis.