Defective interferon signaling in the circulating monocytes of type 2 diabetic mice.

Type 2 diabetes mellitus (T2DM) is associated with poor outcome after stroke. Peripheral monocytes play a critical role in the secondary injury and recovery of damaged brain tissue after stroke, but the underlying mechanisms are largely unclear. To investigate transcriptome changes and molecular networks across monocyte subsets in response to T2DM and stroke, we performed single-cell RNA-sequencing (scRNAseq) from peripheral blood mononuclear cells and bulk RNA-sequencing from blood monocytes from four groups of adult mice, consisting of T2DM model db/db and normoglycemic control db/+ mice with or without ischemic stroke. Via scRNAseq we found that T2DM expands the monocyte population at the expense of lymphocytes, which was validated by flow cytometry. Among the monocytes, T2DM also disproportionally increased the inflammatory subsets with Ly6C+ and negative MHC class II expression (MO.6C+II-). Conversely, monocytes from control mice without stroke are enriched with steady-state classical monocyte subset of MO.6C+II+ but with the least percentage of MO.6C+II- subtype. Apart from enhancing inflammation and coagulation, enrichment analysis from both scRNAseq and bulk RNAseq revealed that T2DM specifically suppressed type-1 and type-2 interferon signaling pathways crucial for antigen presentation and the induction of ischemia tolerance. Preconditioning by lipopolysaccharide conferred neuroprotection against ischemic brain injury in db/+ but not in db/db mice and coincided with a lesser induction of brain Interferon-regulatory-factor-3 in the brains of the latter mice. Our results suggest that the increased diversity and altered transcriptome in the monocytes of T2DM mice underlie the worse stroke outcome by exacerbating secondary injury and potentiating stroke-induced immunosuppression. Significance Statement: The mechanisms involved in the detrimental diabetic effect on stroke are largely unclear. We show here, for the first time, that peripheral monocytes have disproportionally altered the subsets and changed transcriptome under diabetes and/or stroke conditions. Moreover, genes in the IFN-related signaling pathways are suppressed in the diabetic monocytes, which underscores the immunosuppression and impaired ischemic tolerance under the T2DM condition. Our data raise a possibility that malfunctioned monocytes may systemically and focally affect the host, leading to the poor outcome of diabetes in the setting of stroke. The results yield important clues to molecular mechanisms involved in the detrimental diabetic effect on stroke outcome.

Remodeling of the Neurovascular Unit Following Cerebral Ischemia and Hemorrhage.

Formulated as a group effort of the stroke community, the transforming concept of the neurovascular unit (NVU) depicts the structural and functional relationship between brain cells and the vascular structure. Composed of both neural and vascular elements, the NVU forms the blood-brain barrier that regulates cerebral blood flow to meet the oxygen demand of the brain in normal physiology and maintain brain homeostasis. Conversely, the dysregulation and dysfunction of the NVU is an essential pathological feature that underlies neurological disorders spanning from chronic neurodegeneration to acute cerebrovascular events such as ischemic stroke and cerebral hemorrhage, which were the focus of this review. We also discussed how common vascular risk factors of stroke predispose the NVU to pathological changes. We synthesized existing literature and first provided an overview of the basic structure and function of NVU, followed by knowledge of how these components remodel in response to ischemic stroke and brain hemorrhage. A greater understanding of the NVU dysfunction and remodeling will enable the design of targeted therapies and provide a valuable foundation for relevant research in this area.

Sexual dimorphism in immune cell responses following stroke.

Recent bodies of work in regard to stroke have revealed significant sex differences in terms of risk and outcome. While differences in sex hormones have been the focus of earlier research, the reasons for these differences are much more complex and require further identification. This review covers differences in sex related immune responses with a focus on differences in immune cell composition and function. While females are more susceptible to immune related diseases, they seem to have better outcomes from stroke at the experimental level with reduced pro-inflammatory responses. However, at the clinical level, the picture is much more complex with worse neurological outcomes from stroke. While the use of exogenous sex steroids can replicate some of these findings, it is apparent that many other factors are involved in the modulation of immune responses. As a result, more research is needed to better understand these differences and identify appropriate interventions and risk modification.