CCR2 limits inflammatory functions of CD8 TRM cells that impair recognition memory during recovery from WNV encephalitis.

Central nervous system (CNS) resident memory CD8 T cells (T RM ) that express IFN-γ contribute to neurodegenerative processes, including synapse loss, leading to memory impairments. Here, we show that CCR2 signalling in CD8 T RM that persist within the hippocampus after recovery from CNS infection with West Nile virus (WNV) significantly prevents the development of memory impairments. Using CCR2-deficient mice, we determined that CCR2 expression is not essential for CNS T cell recruitment or virologic control during acute WNV infection. However, transcriptomic analyses of forebrain CCR2 + versus CCR2 - CD8 T RM during WNV recovery reveal that CCR2 signalling significantly regulates hippocampal CD8 T RM phenotype and function via extrinsic and intrinsic effects, decreasing the expression of CD103 and granzyme A and IFN-γ, respectively. Consistent with this, WNV-recovered Cd8a cre Ccr2 fl/fl mice exhibit decreased recognition memory. Our findings highlight a neuroprotective role for CCR2 in limiting CD8 T cell-mediated neuroinflammation and cognitive deficits, providing insights into potential therapeutic targets for CNS infections.

West Nile Virus-Induced Expression of Senescent Gene Lgals3bp Regulates Microglial Phenotype within Cerebral Cortex.

Microglia, the resident macrophages of the central nervous system, exhibit altered gene expression in response to various neurological conditions. This study investigates the relationship between West Nile Virus infection and microglial senescence, focusing on the role of LGALS3BP, a protein implicated in both antiviral responses and aging. Using spatial transcriptomics, RNA sequencing and flow cytometry, we characterized changes in microglial gene signatures in adult and aged mice following recovery from WNV encephalitis. Additionally, we analyzed Lgals3bp expression and generated Lgals3bp-deficient mice to assess the impact on neuroinflammation and microglial phenotypes. Our results show that WNV-activated microglia share transcriptional signatures with aged microglia, including upregulation of genes involved in interferon response and inflammation. Lgals3bp was broadly expressed in the CNS and robustly upregulated during WNV infection and aging. Lgals3bp-deficient mice exhibited reduced neuroinflammation, increased homeostatic microglial numbers, and altered T cell populations without differences in virologic control or survival. These data indicate that LGALS3BP has a role in regulating neuroinflammation and microglial activation and suggest that targeting LGALS3BP might provide a potential route for mitigating neuroinflammation-related cognitive decline in aging and post-viral infections.

Microglia at the scene of the crime: what their transcriptomics reveal about brain health.

PURPOSE OF REVIEW: Microglia, which arise from primitive myeloid precursors that enter the central nervous system (CNS) during early development, are the first responders to any perturbance of homeostasis. Although their activation has become synonymous with neurologic disease, it remains unclear whether microglial responses are the cause of or response to neuropathology. Here, we review new insights in the roles of microglia during CNS health and disease, including preclinical studies that transcriptionally profile microglia to define their functional states. RECENT FINDINGS: Converging evidence suggests that innate immune activation of microglia is associated with overlapping alterations in their gene expression profiles regardless of the trigger. Thus, recent studies examining neuroprotective microglial responses during infections and aging mirror those observed during chronic neurologic diseases, including neurodegeneration and stroke. Many of these insights derive from studies of microglial transcriptomes and function in preclinical models, some of which have been validated in human samples. During immune activation, microglia dismantle their homeostatic functions and transition into subsets capable of antigen presentation, phagocytosis of debris, and management of lipid homeostasis. These subsets can be identified during both normal and aberrant microglial responses, the latter of which may persist long-term. The loss of neuroprotective microglia, which maintain a variety of essential CNS functions, may therefore, in part, underlie the development of neurodegenerative diseases. SUMMARY: Microglia exhibit a high level of plasticity, transforming into numerous subsets as they respond to innate immune triggers. Chronic loss of microglial homeostatic functions may underlie the development of diseases with pathological forgetting.

Decreased antiviral immune response within the central nervous system of aged mice is associated with increased lethality of West Nile virus encephalitis.

West Nile virus (WNV) is an emerging pathogen that causes disease syndromes ranging from a mild flu-like illness to encephalitis. While the incidence of WNV infection is fairly uniform across age groups, the risk of lethal encephalitis increases with advanced age. Prior studies have demonstrated age-related, functional immune deficits that limit systemic antiviral immunity and increase mortality; however, the effect of age on antiviral immune responses specifically within the central nervous system (CNS) is unknown. Here, we show that aged mice exhibit increased peripheral organ and CNS tissue viral burden, the latter of which is associated with alterations in activation of both myeloid and lymphoid cells compared with similarly infected younger animals. Aged mice exhibit lower MHCII expression by microglia, and higher levels of PD1 and lower levels of IFNγ expression by WNV-specific CD8+ T cells in the CNS and CD8+ CD45+ cells. These data indicate that the aged CNS exhibits limited local reactivation of T cells during viral encephalitis, which may lead to reduced virologic control at this site.

Regulation of C-X-C chemokine gene expression by keratin 17 and hnRNP K in skin tumor keratinocytes.

High levels of the intermediate filament keratin 17 (K17) correlate with a poor prognosis for several types of epithelial tumors. However, the causal relationship and underlying mechanisms remain undefined. A recent study suggested that K17 promotes skin tumorigenesis by fostering a specific type of inflammation. We report here that K17 interacts with the RNA-binding protein hnRNP K, which has also been implicated in cancer. K17 is required for the cytoplasmic localization of hnRNP K and for its role in regulating the expression of multiple pro-inflammatory mRNAs. Among these are the CXCR3 ligands CXCL9, CXCL10, and CXCL11, which together form a signaling axis with an established role in tumorigenesis. The K17-hnRNP K partnership is regulated by the ser/thr kinase RSK and required for CXCR3-dependent tumor cell growth and invasion. These findings functionally integrate K17, hnRNP K, and gene expression along with RSK and CXCR3 signaling in a keratinocyte-autonomous axis and provide a potential basis for their implication in tumorigenesis.