Identification of senescent, TREM2-expressing microglia in aging and Alzheimer's disease model mouse brain.

Alzheimer's disease (AD) and dementia in general are age-related diseases with multiple contributing factors, including brain inflammation. Microglia, and specifically those expressing the AD risk gene TREM2, are considered important players in AD, but their exact contribution to pathology remains unclear. In this study, using high-throughput mass cytometry in the 5×FAD mouse model of amyloidosis, we identified senescent microglia that express high levels of TREM2 but also exhibit a distinct signature from TREM2-dependent disease-associated microglia (DAM). This senescent microglial protein signature was found in various mouse models that show cognitive decline, including aging, amyloidosis and tauopathy. TREM2-null mice had fewer microglia with a senescent signature. Treating 5×FAD mice with the senolytic BCL2 family inhibitor ABT-737 reduced senescent microglia, but not the DAM population, and this was accompanied by improved cognition and reduced brain inflammation. Our results suggest a dual and opposite involvement of TREM2 in microglial states, which must be considered when contemplating TREM2 as a therapeutic target in AD.

Early Infiltration of Innate Immune Cells to the Liver Depletes HNF4α and Promotes Extrahepatic Carcinogenesis.

Multiple studies have identified metabolic changes within the tumor and its microenvironment during carcinogenesis. Yet, the mechanisms by which tumors affect the host metabolism are unclear. We find that systemic inflammation induced by cancer leads to liver infiltration of myeloid cells at early extrahepatic carcinogenesis. The infiltrating immune cells via IL6-pSTAT3 immune-hepatocyte cross-talk cause the depletion of a master metabolic regulator, HNF4α, consequently leading to systemic metabolic changes that promote breast and pancreatic cancer proliferation and a worse outcome. Preserving HNF4α levels maintains liver metabolism and restricts carcinogenesis. Standard liver biochemical tests can identify early metabolic changes and predict patients' outcomes and weight loss. Thus, the tumor induces early metabolic changes in its macroenvironment with diagnostic and potentially therapeutic implications for the host. SIGNIFICANCE: Cancer growth requires a permanent nutrient supply starting from early disease stages. We find that the tumor extends its effect to the host's liver to obtain nutrients and rewires the systemic and tissue-specific metabolism early during carcinogenesis. Preserving liver metabolism restricts tumor growth and improves cancer outcomes. This article is highlighted in the In This Issue feature, p. 1501.

Alzheimer's disease modification mediated by bone marrow-derived macrophages via a TREM2-independent pathway in mouse model of amyloidosis.

Microglia and monocyte-derived macrophages (MDM) are key players in dealing with Alzheimer's disease. In amyloidosis mouse models, activation of microglia was found to be TREM2 dependent. Here, using Trem2-/-5xFAD mice, we assessed whether MDM act via a TREM2-dependent pathway. We adopted a treatment protocol targeting the programmed cell death ligand-1 (PD-L1) immune checkpoint, previously shown to modify Alzheimer's disease via MDM involvement. Blockade of PD-L1 in Trem2-/-5xFAD mice resulted in cognitive improvement and reduced levels of water-soluble amyloid beta1-42 with no effect on amyloid plaque burden. Single-cell RNA sequencing revealed that MDM, derived from both Trem2-/- and Trem2+/+5xFAD mouse brains, express a unique set of genes encoding scavenger receptors (for example, Mrc1, Msr1). Blockade of monocyte trafficking using anti-CCR2 antibody completely abrogated the cognitive improvement induced by anti-PD-L1 treatment in Trem2-/-5xFAD mice and similarly, but to a lesser extent, in Trem2+/+5xFAD mice. These results highlight a TREM2-independent, disease-modifying activity of MDM in an amyloidosis mouse model.

Immune cell compartmentalization for brain surveillance and protection.

For decades, it was commonly accepted that the brain is secluded from peripheral immune activity and is self-sufficient for its maintenance and repair. This simplistic perception was based on the presence of resident immune cells, the microglia, and barrier systems within the brain, and the assumption that the central nervous system (CNS) lacks lymphatic drainage. This view was revised with the discoveries that higher functions of the CNS, homeostasis and repair are supported by peripheral innate and adaptive immune cells. The findings of bone marrow-derived immune cells in specialized niches, and the renewed observation that a lymphatic drainage system exists within the brain, further contributed to this revised model. In this Review, we describe the immune niches within the brain, the contribution of professional immune cells to brain functions, the bidirectional relationships between the CNS and the immune system and the relevance of immune components to brain aging and neurodegenerative diseases.