Microglia are not necessary for maintenance of blood-brain barrier properties in health, but PLX5622 alters brain endothelial cholesterol metabolism.

Microglia, the resident immune cells of the central nervous system, are intimately involved in the brain's most basic processes, from pruning neural synapses during development to preventing excessive neuronal activity throughout life. Studies have reported both helpful and harmful roles for microglia at the blood-brain barrier (BBB) in the context of disease. However, less is known about microglia-endothelial cell interactions in the healthy brain. To investigate the role of microglia at a healthy BBB, we used the colony-stimulating factor 1 receptor (CSF1R) inhibitor PLX5622 to deplete microglia and analyzed the BBB ultrastructure, permeability, and transcriptome. Interestingly, we found that, despite their direct contact with endothelial cells, microglia are not necessary for the maintenance of BBB structure, function, or gene expression in the healthy brain. However, we found that PLX5622 treatment alters brain endothelial cholesterol metabolism. This effect was independent from microglial depletion, suggesting that PLX5622 has off-target effects on brain vasculature.

Microglia promote anti-tumour immunity and suppress breast cancer brain metastasis.

Breast cancer brain metastasis (BCBM) is a lethal disease with no effective treatments. Prior work has shown that brain cancers and metastases are densely infiltrated with anti-inflammatory, protumourigenic tumour-associated macrophages, but the role of brain-resident microglia remains controversial because they are challenging to discriminate from other tumour-associated macrophages. Using single-cell RNA sequencing, genetic and humanized mouse models, we specifically identify microglia and find that they play a distinct pro-inflammatory and tumour-suppressive role in BCBM. Animals lacking microglia show increased metastasis, decreased survival and reduced natural killer and T cell responses, showing that microglia are critical to promote anti-tumour immunity to suppress BCBM. We find that the pro-inflammatory response is conserved in human microglia, and markers of their response are associated with better prognosis in patients with BCBM. These findings establish an important role for microglia in anti-tumour immunity and highlight them as a potential immunotherapy target for brain metastasis.

Shifting the paradigm: physician-authorized, student-led efforts to provide harm reduction services amidst legislative opposition.

BACKGROUND: For over 30 years, syringe services programs (SSPs) have served as an efficacious intervention for the prevention of HIV and Hepatitis C transmission among persons who use drugs. Despite a strong body of evidence for the effectiveness of SSPs as a preventative public health measure, numerous local and state governments in the United States continue to resist the establishment of new SSPs and aggressively pursue the closure of those already in operation. COMMENTARY: In Orange County, California, local officials have repeatedly mobilized in opposition of the establishment of syringe access - thereby hindering access to healthcare for thousands of predominantly unhoused individuals. The county was previously served by the Orange County Needle Exchange Program from 2016 until 2018 when a civil suit brought by the Orange County Board of Supervisors resulted in the closure of the program. For more than 2 years, persons who inject drugs in Orange County lacked reliable access to clean syringes, placing them at increased risk for contracting HIV and Hepatitis C. Here, we comment on the ongoing effort to restore syringe access in Orange County. This collaborative physician-directed endeavor has brought together students and community volunteers to provide vital harm reduction services to a remarkably underserved population. Since the reestablishment of syringe access in Orange County by the Harm Reduction Institute, new legal barriers have arisen including the passage of new municipal legislation banning the operation of syringe exchanges. We are well-equipped to overcome these obstacles. This work serves as an affirmation of assertions made by previous authors regarding the unique qualifications of medical & graduate students as effective harm reductionists. CONCLUSION: Harm reduction services are vital to the health and well-being of people who use drugs. The provision of these services should not be impeded by legislative interference by municipal, county, or state governments.