Aurora Semerano, MD

European Stroke Organisation Conference

May 4-6, 2022
Scientific Session – ISNI-ESO Joint Symposium: The immunology of stroke – an update

This year, ESOC hosted a Joint Symposium with the International Society of Neuroimmunology (ISNI), to discuss the most recent advances on the immunology of stroke. The session, chaired by Craig Smith (United Kingdom) and Corinne Benakis (Germany), was conducted by a great line-up of speakers, who discussed the role of inflammation in stroke both in the brain and at the systemic level, the important consequences of immune involvement, and the perspectives of immunotherapies in stroke.

Adam Denes (Hungary) focused on the close interactions between microglial cells and the neurovascular unit: Among their heterogenous functions in health and disease, indeed, microglia have been discovered to have close contact with cells of cerebral blood vessels (smooth muscle cells, astrocyte, pericytes, endothelial cells). As a result, it is likely that microglia have an influence on neurovascular coupling by sensing hypercapnia, whereas microglial dysfunction may impair hypercapnia-induced vasodilation in the cerebral cortex. This newly recognized function might be pivotal in stroke, especially in contributing to the so-called no-reflow phenomenon. Importantly, variants of microglial or microglia-regulated genes show strong associations with disturbance in cerebral blood flow. Further investigations, including genome wide association studies in humans, are warranted to explore correlation between gene variants in microglia and small vessel and neurodegenerative disorders.

In his talk, Stuart Allan (United Kingdom) shifted from the brain to the periphery. Indeed, the systemic immune response induced by stroke contributes to stroke outcome in different ways, including the modulation of post-stroke infections, with great impact on mortality. Previously understudied, Dr. Allen presented new data about B cells in the acute phase of ischemic stroke. Marginal zone-like B cells, a cellular subtype relevant for the defense against infections, result to be reduced after stroke in patients, and they phenotypically change towards a hyporesponsive behavior, likely mediated by the release of noradrenaline. As a perspective, frequency of specific B cell subsets may be studied as predictors of outcome, and a potential approach through early administration of IgM is suggested as a potential therapy against post-stroke infections.

Andreas Meisel (Germany) provided an overview on what we have learned so far about immunotherapy in stroke. Despite many efforts, immunotherapeutic strategies that appeared to be beneficial in experimental stroke have not turned out to be convincing in human stroke patients. Many reasons are suggested for these failures, and more knowledge is needed about cellular and molecular targets, limitations of animal models, timing and functional role of signaling cascades. Importantly, the potentially opposing effects of immunotherapies in the ischemic brain and in peripheral organs should be taken into careful consideration when designing proper studies in order to address neuroinflammation without compromising the host defense.

Neuroinflammation has been recognized as a relevant pathophysiological mechanism also after intracerebral hemorrhage. Lauren Sansing (United States) dissected the main players which have been identified so far. Morphological changes of microglia occur within 20 minutes, and circulating monocytes are rapidly recruited and activated after intracerebral hemorrhage, whereas in later phases, macrophages are actively involved in phagocytosis of hemorrhagic debris. NK cells have also been discovered as main characters since they contribute to blood brain breakdown in the acute phase. Long distance cross talks exist between the brain and the periphery after intracerebral hemorrhage, which can lead to phenotypical changes of neutrophils in the bone marrow via IL-27. Finally, longitudinal transcriptomics in hemorrhagic samples from minimally invasive neurosurgery helped to define the time course of myeloid activation in the human brain, revealing a conserved progression of immune responses from proinflammatory to pro-recovery states.

Arthur Liesz (Germany) spun the clock forward and directed the attention on the chronic phase of ischemic stroke. A pathophysiological explanation of translational failures in stroke immunology is provided: Whereas in the experimental studies outcome assessment yields on the evaluation of ischemic lesion acutely after stroke, human trials evaluate chronic recovery and long-term outcome.  Stroke, indeed, induces a strong chronic inflammation within the brain. Previous experimental approaches that appeared successful in the acute phase (namely, blocking leukocyte infiltration, lymphocyte and microglial depletion) resulted in impaired recovery in terms of connectivity in the chronic phase. The divergent functions of neuroinflammation in acute vs. chronic phase should be dissected for future immunomodulatory therapies in stroke.