Human genetics and preclinical studies have identified key contributions of TREM2 to several neurodegenerative conditions, inspiring efforts to modulate TREM2 therapeutically. Here, we characterize the activities of three TREM2 agonist antibodies in multiple mixed-sex mouse models of Alzheimer's disease (AD) pathology and remyelination. Receptor activation and downstream signaling are explored in vitro, and active dose ranges are determined in vivo based on pharmacodynamic responses from microglia. For mice bearing amyloid-β (Aβ) pathology (PS2APP) or combined Aβ and tau pathology (TauPS2APP), chronic TREM2 agonist antibody treatment had limited impact on microglia engagement with pathology, overall pathology burden, or downstream neuronal damage. For mice with demyelinating injuries triggered acutely with lysolecithin, TREM2 agonist antibodies unexpectedly disrupted injury resolution. Likewise, TREM2 agonist antibodies limited myelin recovery for mice experiencing chronic demyelination from cuprizone. We highlight the contributions of dose timing and frequency across models. These results introduce important considerations for future TREM2-targeting approaches.
Copyright © 2024 the authors.

Inflammasomes are macromolecular complexes that assemble upon the detection of cytoplasmic pathogen-associated or danger-associated signals and induce a necrotic type of cell death termed pyroptosis, facilitating pro-inflammatory cytokine release. Inflammasomes play a critical role in innate immunity and inflammatory response; however, they have also been associated with multiple diseases, including autoinflammatory and neurodegenerative conditions. In the following chapter, we describe methods to detect inflammasome activation and its downstream effects, including detection of ASC oligomerization, detection of activated caspase-1 and cleaved IL-1β, as well as read-outs for inflammasome-mediated cell death.
© 2024. The Author(s), under exclusive license to Springer Science+Business Media, LLC, part of Springer Nature.

Type I interferon (IFN-I) production by plasmacytoid dendritic cells (pDCs) occurs during viral infection, in response to Toll-like receptor 7 (TLR7) stimulation and is more vigorous in females than in males. Whether this sex bias persists in ageing people is currently unknown. In this study, we investigated the effect of sex and aging on IFN-α production induced by PRR agonist ligands.
In a large cohort of individuals from 19 to 97 years old, we measured the production of IFN-α and inflammatory cytokines in whole-blood upon stimulation with either R-848, ODN M362 CpG-C, or cGAMP, which activate the TLR7/8, TLR9 or STING pathways, respectively. We further characterized the cellular sources of IFN-α.
We observed a female predominance in IFN-α production by pDCs in response to TLR7 or TLR9 ligands. The higher TLR7-driven IFN-α production in females was robustly maintained across ages, including the elderly. The sex-bias in TLR9-driven interferon production was lost after age 60, which correlated with the decline in circulating pDCs. By contrast, STING-driven IFN-α production was similar in both sexes, preserved with aging, and correlated with circulating monocyte numbers. Indeed, monocytes were the primary cellular source of IFN-α in response to cGAMP.
We show that the sex bias in the TLR7-induced IFN-I production is strongly maintained through ages, and identify monocytes as the main source of IFN-I production via STING pathway.
This work was supported by grants from Région Occitanie/Pyrénées-Méditerranée (#12052910, Inspire Program #1901175), University Paul Sabatier, and the European Regional Development Fund (MP0022856).
Copyright © 2022 The Authors. Published by Elsevier B.V. All rights reserved.