Biology subjects

Childs, T.

Publications and source records attributed to Childs, T..

3 recordsLinked to original sources

bioRxiv2024

Thymic stromal lymphopoietin contributes to endometriotic lesion proliferation and disease-associated inflammation.

Endometriosis is a chronic disorder in which endometrial-like tissue presents outside the uterus. Patients with endometriosis have been shown to exhibit aberrant immune responses within the lesion microenvironment and in circulation which contribute to the development of endometriosis. Thymic stromal lymphopoietin (TSLP) is an alarmin involved in cell proliferation and the induction of Th2 inflammation in various diseases, such as asthma, atopic dermatitis, pancreatic and breast cancer. Recent studies have detected TSLP within endometriotic lesions and shown that its concentrations are elevated in the peritoneal fluid of patients compared to controls. However, its role in disease pathophysiology remains unclear. Here, we compared TSLP expression in endometriotic lesions to matched patient endometrium and control endometrium samples. We also assessed its effect on the proliferation and apoptosis of human endometriosis-representative cell lines, as well as on lesion development and inflammation in a mouse model of the disease. We demonstrated that TSLP expression was elevated in the stroma of patient endometriotic lesions compared to control endometrial samples. In cell lines, TSLP treatment reduced the apoptosis of endometrial stromal cells and promoted the proliferation of THP-I cells. In mice induced with endometriosis, TSLP treatment induced a Th2 immune response within the lesion microenvironment, and led to TSLP receptor modulation in macrophages, dendritic cells, and CD4+ T cells. Furthermore, treatment increased murine endometriotic lesion proliferation. Overall, these results suggest that TSLP modulates the endometriotic lesion microenvironment and promotes a Th2 immune response that could support lesion development. KEY POINTSO_LITSLP is overexpressed in the stroma of human endometriotic lesions; C_LIO_LITSLP promotes the survival of human endometrial stromal and THP-I cell lines; C_LIO_LITSLP induces Th2 inflammation and lesion proliferation. C_LI

immunology↗

bioRxiv2022

Microglia Detect Externalized Phosphatidylserine on Synapses for Elimination via TREM2 in Alzheimer's Disease Models

Genetic studies implicate phagocytosis pathways in microglia to be a major Alzheimers disease (AD)-associated process. Microglia phagocytose synapses in AD mouse models, suggesting a role for microglia in region-specific synapse loss, a pathological hallmark of AD. However, whether specific synapses are targeted for elimination, and if so, how, remains to be elucidated. Here, we show that synapses externalize phosphatidylserine (PtdSer) upon challenge by {beta}-amyloid oligomers, which are then selectively engulfed by microglia. Mechanistically, we find that Triggering Receptor Expressed on Myeloid Cells 2 (TREM2) is critical for microglia to sense and preferentially engulf AD synapses. In brains of mice and humans, TREM2 dysfunction leads to exacerbation of apoptotic synapses. Our work altogether suggests a fundamental role for microglia as brain-resident macrophages to remove damaged synapses in AD. We provide mechanistic insight into how TREM2 variants associated with increased risk of developing AD may contribute to defective microglia-synapse function. One-Sentence summaryMicroglia selectively engulf synapses in Alzheimer-like mouse brains via PtdSer-TREM2 signaling.

neuroscience↗

bioRxiv2022

Perivascular SPP1 Mediates Microglial Engulfment of Synapses in Alzheimers Disease Models

Microglia are phagocytes of the brain parenchyma, where they interact with neurons to engulf synapses in a context-dependent manner. Genetic studies in Alzheimers disease (AD) highlight dysfunctional phagocytic signaling in myeloid cells as disease-associated pathway. In AD models, there is a region-specific reactivation of microglia-synapse phagocytosis involving complement; however, what drives microglia-synapse engulfment remains unknown. Here, we show that SPP1 (Osteopontin), a glycoprotein associated with inflammation, is regionally upregulated and modulates microglial synaptic engulfment in AD mouse models. Ultrastructural examination revealed SPP1 expression predominantly by perivascular macrophages, a subtype of border-associated macrophages, in the hippocampus of mice and patient tissues. Cell-cell interaction networks of single-cell transcriptomics data suggested that perivascular SPP1 drives microglial functional states in the hippocampal microenvironment of AD mice. Absence of Spp1 expression resulted in failure of microglia to mediate synaptic phagocytosis. This study suggests a critical role for perivascular SPP1 in neuroimmune crosstalk in AD-relevant context.

neuroscience↗