# Peripheral endotoxin exposure in mice activates crosstalk between phagocytes in the brain and periphery

## TL;DR

Exposure to endotoxin in mice activates communication between brain and peripheral immune cells, suggesting a role for non-brain immune cells in neuroinflammation.

## Contribution

The study reveals novel crosstalk between microglia and peripheral phagocytes during neuroinflammation triggered by peripheral endotoxin exposure.

## Key findings

- Peripheral phagocytes in the brain show transcriptional profiles similar to microglia during LPS-induced neuroinflammation.
- Probable crosstalk between microglia and peripheral phagocytes is activated, while homotypic microglial communication is reduced.
- Peripheral inflammation preferentially triggers microglia signaling to peripheral phagocytes, linked to brain infiltration of these cells.

## Abstract

Inflammation is a central process of many neurological diseases, and a growing number of studies suggest that non-brain-resident immune cells may contribute to this neuroinflammation. However, the unique contributions of specific immune cell subsets to neuroinflammation are presently unknown, and it is unclear how communication between brain-resident and non-resident immune cells underlies peripheral immune cell involvement in neuroinflammation.

In this study, we employed the well-established model of lipopolysaccharide (LPS)-induced neuroinflammation and captured brain-resident and non-resident immune cells from the brain and its vasculature by magnetically enriching cell suspensions from the non-perfused brain for CD45 + cells. Then, we identified immune subtype-specific neuroinflammatory processes using single-cell genomics and predicted the crosstalk between immune cell subtypes by analyzing the simultaneous expression of ligands and receptors.

We observed a greater abundance of peripheral phagocytes associated with the brain in this model of neuroinflammation, and report that these professional phagocytes activated similar transcriptional profiles to microglia during LPS-induced neuroinflammation. And, we observed that the probable crosstalk between microglia and peripheral phagocytes was activated in this model while homotypic microglial communication was likely to be decreased.

Our novel findings reveal that microglia signaling to non-brain-resident peripheral phagocytes is preferentially triggered by peripheral inflammation, which is associated with brain infiltration of peripheral cells. Overall, our study supports the involvement of peripheral immune cells in neuroinflammation and suggests several possible molecular signaling pathways between microglia and peripheral cells that may facilitate central-peripheral crosstalk during inflammation. Examining these molecular mediators in human disease and other rodent models may reveal novel targets that modify brain health, especially in comorbidities characterized by peripheral inflammation.