CNS-peripheral immune interactions in hemorrhagic stroke

Abstract

Stroke is a sudden and rapidly progressing ischemic or hemorrhagic cerebrovascular disease. When stroke damages the brain, the immune system becomes hyperactive, leading to systemic inflammatory response and immunomodulatory disorders, which could significantly impact brain damage, recovery, and prognosis of stroke. Emerging researches suggest that ischemic stroke-induced spleen contraction could activate a peripheral immune response, which may further aggravate brain injury. This review focuses on hemorrhagic strokes including intracerebral hemorrhage (ICH) and subarachnoid hemorrhage (SAH) and discusses the central nervous system-peripheral immune interactions after hemorrhagic stroke induction. First, inflammatory progression after ICH and SAH is investigated. As a part of this review, we summarize the various kinds of inflammatory cell infiltration to aggravate brain injury after blood-brain barrier interruption induced by hemorrhagic stroke. Then, we explore hemorrhagic stroke-induced systemic inflammatory response syndrome (SIRS) and discuss the interactions of CNS and peripheral inflammatory response. In addition, potential targets related to inflammatory response for ICH and SAH are discussed in this review, which may lead to novel therapeutic strategies for hemorrhagic stroke.

Keywords: Systemic inflammation; immune dysregulation; intracerebral hemorrhage; stroke; subarachnoid hemorrhage.

Figure 1.

Inflammatory response after hemorrhagic stroke. In the brain parenchyma, neuronal injury secretes damage-associated molecular patterns (DAMPs), which could activate microglia. Microglia secrete pro-inflammatory cytokines and factors, activating astrocytes. Activation and dysfunction of astrocytes contribute to blood-brain barrier (BBB) disruption, causing infiltration of peripheral immune cells. Reactive astrocytes also form a glial scar. However, the “N2” neutrophils, Tregs, and “M2” Macrophages secrete anti-inflammatory cytokines and factors, playing a role in limiting neuroinflammation. In the periphery, Macrophages and Neutrophils secrete IL-6 and TNF-α, promoting the differentiation of lymphocytes into cytotoxic T cells and Ig-producing B cells. ROS and MMP-9 secreted by neutrophils also contribute to the dysfunction of the blood-brain barrier. ICH: intracerebral hemorrhage; SAH: subarachnoid hemorrhage; DAMPs: damage-associated molecular patterns; IL: interleukin; TNF: tumor necrosis factor; INF: interferon; ROS: reactive oxygen species; MMP: matrix metalloproteinases; Ig: immune globulin; Gal: galectin; HMGB: high-mobility group box.

Figure 2.

Hemorrhagic stroke-induced systemic inflammatory response syndrome. ICH and SAH brain promote the spleen to generate lymphocytes by the autonomic nervous system, CNS antigens, and chemokines, causing systemic inflammation and immune response. The systemic inflammatory response contributes to pulmonary infection, kidney infection, and cardiac dysfunction. Circulating pro-inflammatory cytokine/chemokine leads to dysbiosis and gut inflammation, while dysbiosis and intestinal inflammation also increase the associated cytokines/chemokines. All these circulating pro-inflammatory cytokines also increase the pro-inflammatory T cells, pro-inflammatory macrophages, and classical monocytes, which could access the brain parenchyma across the dysfunctional blood-brain barrier. ICH: intracerebral hemorrhage; SAH: subarachnoid hemorrhage; BBB: blood-brain barrier; MAP: microtubule-associated protein; NR: N-methyl-D-aspartate receptor; MBP: myelin basic protein; MOG: myelin oligodendrocyte glycoprotein.