Systemic inflammation after stroke: implications for post-stroke comorbidities

Abstract

Immunological mechanisms have come into the focus of current translational stroke research, and the modulation of neuroinflammatory pathways has been identified as a promising therapeutic approach to protect the ischemic brain. However, stroke not only induces a local neuroinflammatory response but also has a profound impact on systemic immunity. In this review, we will summarize the consequences of ischemic stroke on systemic immunity at all stages of the disease, from onset to long-term outcome, and discuss underlying mechanisms of systemic brain-immune communication. Furthermore, since stroke commonly occurs in patients with multiple comorbidities, we will also overview the current understanding of the potential role of systemic immunity in common stroke-related comorbidities, such as cardiac dysfunction, atherosclerosis, diabetes, and infections. Finally, we will highlight how targeting systemic immunity after stroke could improve long-term outcomes and alleviate comorbidities of stroke patients.

Keywords: inflammation; long-term outcome; post-stroke comorbidities; stroke; systemic immunity.

Figure 1. Main hallmarks of poststroke systemic inflammation over time

The peripheral immune response to stroke is initiated within minutes after stroke onset. DAMP are originated from dying or stressed cells within the ischemic brain or actively secreted by immune cells upon activation. Circulating DAMPs activate peripheral immune cells and provoke a massive expression and release of pro‐inflammatory cytokines into the bloodstream. Within the acute phase, stroke also induces the mobilization of more leukocytes from the spleen and the bone marrow as well as the activation of neurogenic pathways. In the subacute phase, within hours to days after stroke onset, a state of immunosuppression is triggered. The prolonged overactivation of neurogenic pathways as well as DAMP and other pro‐inflammatory mediators acutely released after stroke gradually induce lymphopenia due to massive cell death and the pronounced bias towards the monocyte differentiation pathway in bone marrow hematopoiesis. The is also a disbalance between Type 1 (Th1) and Type 2 (Th2) helper T cells and circulating monocytes are less capable of providing costimulatory signals. Later in time, a long‐term phase compromising peripheral immunity is characterized by chronic and sustained high levels of DAMP and pro‐inflammatory cytokines.

Figure 2. Mechanisms contributing to post‐stroke immune system activation

Key effects triggered by the activation of the autonomic nervous system (black) or the circulating DAMP (red) in blood, spleen, bone marrow and gut, primary organs of the immune system.

Figure 3. The stroke‐induced systemic inflammation represents a risk factor for the development of inflammation‐related comorbidities after stroke