Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) emerged late in 2019 and caused the coronavirus disease 2019 (COVID-19) pandemic that has so far claimed approximately 20 million lives. Vaccines were developed quickly, became available in the end of 2020, and had a tremendous impact on protection from SARS-CoV-2 mortality but with emerging variants the impact on morbidity was diminished. Here I review what we learned from COVID-19 from a vaccinologist's perspective.

Recent evidence implicates cranial border immune compartments in the meninges, choroid plexus, circumventricular organs, and skull bone marrow in several neuroinflammatory and neoplastic diseases. Their pathogenic importance has also been described for cardiovascular diseases such as hypertension and stroke. In this review, we will examine the cellular composition of these cranial border immune niches, the potential pathways through which they might interact, and the evidence linking them to cardiovascular disease.

Despite years of encouraging translational research, ischemic stroke still remains as one of the highest unmet medical needs nowadays, causing a tremendous burden to health care systems worldwide. Following an ischemic insult, a complex signaling pathway emerges leading to highly interconnected thrombotic as well as neuroinflammatory signatures, the so-called thromboinflammatory cascade. Here, we thoroughly review the cell-specific and time-dependent role of different immune cell types, i.e., neutrophils, macrophages, T and B cells, as key thromboinflammatory mediators modulating the neuroinflammatory response upon stroke. Similarly, the relevance of platelets and their tight crosstalk with a variety of immune cells highlights the relevance of this cell-cell interaction during microvascular dysfunction, neovascularization, and cellular adhesion. Ultimately, we provide an up-to-date overview of therapeutic approaches mechanistically targeting thromboinflammation currently under clinical translation, especially focusing on phase I to III clinical trials.

Stroke is the second leading cause of death worldwide and a leading cause of disability. Clinical and experimental studies highlighted the complex role of the immune system in the pathophysiology of stroke. Ischemic brain injury leads to the release of cell-free DNA, a damage-associated molecular pattern, which binds to pattern recognition receptors on immune cells such as toll-like receptors and cytosolic inflammasome sensors. The downstream signaling cascade then induces a rapid inflammatory response. In this review, we are highlighting the characteristics of cell-free DNA and how these can affect a local as well as a systemic response after stroke. For this purpose, we screened literature on clinical studies investigating cell-free DNA concentration and properties after brain ischemia. We report the current understanding for mechanisms of DNA uptake and sensing in the context of post-stroke inflammation. Moreover, we compare possible treatment options targeting cell-free DNA, DNA-sensing pathways, and the downstream mediators. Finally, we describe clinical implications of this inflammatory pathway for stroke patients, open questions, and potential future research directions.

Neuronal plasticity is critical for the maintenance and modulation of brain activity. Emerging evidence indicates that glial cells actively shape neuroplasticity, allowing for highly flexible regulation of synaptic transmission, neuronal excitability, and network synchronization. Astrocytes regulate synaptogenesis, stabilize synaptic connectivity, and preserve the balance between excitation and inhibition in neuronal networks. Microglia, the brain-resident immune cells, continuously monitor and sculpt synapses, allowing for the remodeling of brain circuits. Glia-mediated neuroplasticity is driven by neuronal activity, controlled by a plethora of feedback signaling mechanisms and crucially involves extracellular matrix remodeling in the central nervous system. This review summarizes the key findings considering neurotransmission regulation and metabolic support by astrocyte-neuronal networks, and synaptic remodeling mediated by microglia. Novel data indicate that astrocytes and microglia are pivotal for controlling brain function, indicating the necessity to rethink neurocentric neuroplasticity views.

Aging is associated to progressive changes impairing fundamental cellular and tissue functions, and the relationships amongst them through the vascular and immune systems. Aging factors are key to understanding the pathophysiology of stroke since they increase its risk and worsen its functional outcome. Most currently recognised hallmarks of aging are also involved in the cerebral responses to stroke. Notably, age-associated chronic low-grade inflammation is related to innate immune responses highlighted by induction of type-I interferon. The interferon program is prominent in microglia where it interrelates cell damage, danger signals, and phagocytosis with immunometabolic disturbances and inflammation. Microglia engulfment of damaged myelin and cell debris may overwhelm the cellular capacity for waste removal inducing intracellular lipid accumulation. Acute inflammation and interferon-stimulated gene expression are also typical features of acute stroke, where danger signal recognition by microglia trigger immunometabolic alterations underscored by lipid droplet biogenesis. Aging reduces the capacity to control these responses causing increased and persistent inflammation, metabolic dysregulation, and impaired cellular waste disposal. In turn, chronic peripheral inflammation during aging induces immunosenescence further worsening stroke-induced immunodepression, thus increasing the risk of post-stroke infection. Aging also alters gut microbiota composition inducing dysbiosis. These changes are enhanced by age-related diseases, such as atherosclerosis and type-II diabetes, that further promote vascular aging, predispose to stroke, and exacerbate brain inflammation after stroke. Current advances in aging research suggest that some age-associated alterations may be reversed. Future work will unravel whether such evolving anti-aging research may enable designing strategies to improve stroke outcome in the elderly.

In ischemic stroke, the primary neuronal injury caused by the disruption of energy supply is further exacerbated by secondary sterile inflammation. The inflammatory cascade is largely initiated by the purine adenosine triphosphate (ATP) which is extensively released to the interstitial space during brain ischemia and functions as an extracellular danger signaling molecule. By engaging P2 receptors, extracellular ATP activates microglia leading to cytokine and chemokine production and subsequent immune cell recruitment from the periphery which further amplifies post-stroke inflammation. The ectonucleotidases CD39 and CD73 shape and balance the inflammatory environment by stepwise degrading extracellular ATP to adenosine which itself has neuroprotective and anti-inflammatory signaling properties. The neuroprotective effects of adenosine are mainly mediated through A1 receptors and inhibition of glutamatergic excitotoxicity, while the anti-inflammatory capacities of adenosine have been primarily attributed to A2A receptor activation on infiltrating immune cells in the subacute phase after stroke. In this review, we summarize the current state of knowledge on the ATP-adenosine axis in ischemic stroke, discuss contradictory results, and point out potential pitfalls towards translating therapeutic approaches from rodent stroke models to human patients.

The complexity and plasticity of the tumor microenvironment (TME) make it difficult to fully understand the intratumoral regulation of different cell types and their activities. Macrophages play a crucial role in the signaling dynamics of the TME. Among the different subtypes of macrophages, tumor-associated macrophages (TAMs) are often associated with poor prognosis, although some subtypes of TAMs can at the same time improve treatment responsiveness and lead to favorable clinical outcomes. TAMs are key regulators of cancer cell proliferation, metastasis, angiogenesis, extracellular matrix remodeling, tumor metabolism, and importantly immunosuppression in the TME by modulating various chemokines, cytokines, and growth factors. TAMs have been identified as a key contributor to resistance to chemotherapy and cancer immunotherapy. In this review article, we aim to discuss the mechanisms by which TAMs regulate innate and adaptive immune signaling in the TME and summarize recent preclinical research on the development of therapeutics targeting TAMs and tumor metabolism.