Alzheimer’s disease, obesity-related metabolic syndrome, and cancer are the leading causes of death and among the most costly medical conditions in the Western world. In all three cases, recent ...discoveries establish the TREM2 receptor as a major pathology-induced immune signaling hub that senses tissue damage and activates robust immune remodeling in response to it. In this review, we summarize and question what is known and remains to be discovered about TREM2 signaling pathway, track the consequences of its activation in physiological niches and pathological contexts, and highlight the promising potential of therapeutic manipulation of TREM2 signaling.
TREM2 has been associated with altered signaling in a number of diseases. This Perspective summarizes our current understanding of this receptor and the pathways it modulates.
Neuroinflammation is common to various diseases of the central nervous system (CNS), but its imprecise definition has led to many misconceptions in research and clinical approaches. It is now ...recognized that neuroinflammation in chronic neurodegenerative conditions, including Alzheimer's disease (AD) and age-related dementia, is distinct from the inflammation that accompanies relapsing–remitting multiple sclerosis (RRMS), and its experimental animal model, experimental autoimmune encephalomyelitis (EAE). Here, we discuss the discrete features of inflammation in different CNS pathologies, given the current understanding of the CNS–immune crosstalk; the roles of the immune cells that are involved, their phenotypes, and their location and route of entry to the CNS. Understanding the term neuroinflammation to encompass a broad range of disease-specific conditions is essential for finding effective therapeutic approaches for these pathologies.
A major challenge in the field of neurodegenerative diseases and brain aging is to identify the body’s intrinsic mechanism that could sense the central nervous system (CNS) damage early and protect ...the brain from neurodegeneration. Accumulating evidence suggests that disease-associated microglia (DAM), a recently identified subset of CNS resident macrophages found at sites of neurodegeneration, might play such a protective role. Here, we propose that microglia are endowed with a dedicated sensory mechanism, which includes the Trem2 signaling pathway, to detect damage within the CNS in the form of neurodegeneration-associated molecular patterns (NAMPs). Combining data from transcriptional analysis of DAM at single-cell level and from human genome-wide association studies (GWASs), we discuss potential function of different DAM pathways in the diseased brain and outline how manipulating DAM may create new therapeutic opportunities.
Recent analyses of CNS immune cells in neurodegenerative conditions have identified a subset of microglia showing a unique transcriptional and functional signature, disease-associated microglia (DAM). This perspective proposes a role for DAM as a sensor of early CNS damage and discusses the therapeutic potential of modulating DAM function in CNS diseases.
Viruses are a constant threat to global health as highlighted by the current COVID-19 pandemic. Currently, lack of data underlying how the human host interacts with viruses, including the SARS-CoV-2 ...virus, limits effective therapeutic intervention. We introduce Viral-Track, a computational method that globally scans unmapped single-cell RNA sequencing (scRNA-seq) data for the presence of viral RNA, enabling transcriptional cell sorting of infected versus bystander cells. We demonstrate the sensitivity and specificity of Viral-Track to systematically detect viruses from multiple models of infection, including hepatitis B virus, in an unsupervised manner. Applying Viral-Track to bronchoalveloar-lavage samples from severe and mild COVID-19 patients reveals a dramatic impact of the virus on the immune system of severe patients compared to mild cases. Viral-Track detects an unexpected co-infection of the human metapneumovirus, present mainly in monocytes perturbed in type-I interferon (IFN)-signaling. Viral-Track provides a robust technology for dissecting the mechanisms of viral-infection and pathology.
Display omitted
•Viral-Track: a computational framework to analyze host-viral infection maps•Viral-Track sorts infected from bystander cells and reveals virus-induced expression•SARS-CoV-2 infects epithelial cells and alters immune landscape in severe patients•Co-infection of SARS-Cov-2 and hMPV affects monocytes and dampens interferon response
A computational framework that allows for the identification and characterization of virus-infected cells as well as bystander cell responses reveals how SARS-CoV-2 alters the immune responses of patients.
Immune cells patrol the brain and can support its function, but can we modulate brain-immune communication to fight neurological diseases? Here, we briefly discuss the mechanisms orchestrating the ...cross-talk between the brain and the immune system and describe how targeting this interaction in a well-controlled manner could be developed as a universal therapeutic approach to treat neurodegeneration.
Immune cells residing in white adipose tissue have been highlighted as important factors contributing to the pathogenesis of metabolic diseases, but the molecular regulators that drive adipose tissue ...immune cell remodeling during obesity remain largely unknown. Using index and transcriptional single-cell sorting, we comprehensively map all adipose tissue immune populations in both mice and humans during obesity. We describe a novel and conserved Trem2+ lipid-associated macrophage (LAM) subset and identify markers, spatial localization, origin, and functional pathways associated with these cells. Genetic ablation of Trem2 in mice globally inhibits the downstream molecular LAM program, leading to adipocyte hypertrophy as well as systemic hypercholesterolemia, body fat accumulation, and glucose intolerance. These findings identify Trem2 signaling as a major pathway by which macrophages respond to loss of tissue-level lipid homeostasis, highlighting Trem2 as a key sensor of metabolic pathologies across multiple tissues and a potential therapeutic target in metabolic diseases.
Display omitted
•scRNA-seq reveals a dynamic adipose tissue immune cell atlas in mice and humans•Massive induction of a conserved LAM program during obesity•The lipid receptor Trem2 is essential for LAM protective functions•LAMs counteract inflammation, adipocyte hypertrophy, and metabolic disease
A single-cell atlas of human and mouse adipose tissue uncovers protective lipid-associated macrophages (LAMs), which perform lipid uptake and metabolism to prevent adipocyte hypertrophy, inflammation, and systemic metabolic dysregulation in a Trem2 signaling-dependent manner.
Aging-associated cognitive decline is affected by factors produced inside and outside the brain. By using multiorgan genome-wide analysis of aged mice, we found that the choroid plexus, an interface ...between the brain and the circulation, shows a type I interferon (IFN-I)–dependent gene expression profile that was also found in aged human brains. In aged mice, this response was induced by brain-derived signals, present in the cerebrospinal fluid. Blocking IFN-I signaling within the aged brain partially restored cognitive function and hippocampal neurogenesis and reestablished IFN-II–dependent choroid plexus activity, which is lost in aging. Our data identify a chronic aging-induced IFN-I signature, often associated with antiviral response, at the brain’s choroid plexus and demonstrate its negative influence on brain function, thereby suggesting a target for ameliorating cognitive decline in aging.
Microglia, the resident myeloid cells of the central nervous system, play important roles in life-long brain maintenance and in pathology. Despite their importance, their regulatory dynamics during ...brain development have not been fully elucidated. Using genome-wide chromatin and expression profiling coupled with single-cell transcriptomic analysis throughout development, we found that microglia undergo three temporal stages of development in synchrony with the brain--early, pre-, and adult microglia--which are under distinct regulatory circuits. Knockout of the gene encoding the adult microglia transcription factor MAFB and environmental perturbations, such as those affecting the microbiome or prenatal immune activation, led to disruption of developmental genes and immune response pathways. Together, our work identifies a stepwise microglia developmental program integrating immune response pathways that may be associated with several neurodevelopmental disorders.
Non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH) are prevalent liver conditions that underlie the development of life-threatening cirrhosis, liver failure and liver ...cancer. Chronic necro-inflammation is a critical factor in development of NASH, yet the cellular and molecular mechanisms of immune dysregulation in this disease are poorly understood. Here, using single-cell transcriptomic analysis, we comprehensively profiled the immune composition of the mouse liver during NASH. We identified a significant pathology-associated increase in hepatic conventional dendritic cells (cDCs) and further defined their source as NASH-induced boost in cycling of cDC progenitors in the bone marrow. Analysis of blood and liver from patients on the NAFLD/NASH spectrum showed that type 1 cDCs (cDC1) were more abundant and activated in disease. Sequencing of physically interacting cDC-T cell pairs from liver-draining lymph nodes revealed that cDCs in NASH promote inflammatory T cell reprogramming, previously associated with NASH worsening. Finally, depletion of cDC1 in XCR1
mice or using anti-XCL1-blocking antibody attenuated liver pathology in NASH mouse models. Overall, our study provides a comprehensive characterization of cDC biology in NASH and identifies XCR1
cDC1 as an important driver of liver pathology.
Phagocytic microglia such as proliferative region-associated microglia and disease-associated microglia appear in the brain transiently during development and across various brain pathologies, but ...their function and degree of plasticity remain unclear. In this issue of Immunity, Barclay et al. established a novel Clec7a-CreERT2 mouse line to uncover the plasticity of this cell state and its role in a model of myelin injury.
Phagocytic microglia such as proliferative region-associated microglia and disease-associated microglia appear in the brain transiently during development and across various brain pathologies, but their function and degree of plasticity remain unclear. In this issue of Immunity, Barclay et al. established a novel Clec7a-CreERT2 mouse line to uncover the plasticity of this cell state and its role in a model of myelin injury.
PDF
