A Newly Identified Body-to-Brain Circuit for Regulating Inflammation
Post by Shahin Khodaei
The takeaway
Communication between the brain and the body plays a key role in the immune response: information about bodily inflammation is delivered to the brain, which can subsequently adjust inflammation in the body to an appropriate level.
What's the science?
Inflammation, a component of innate immunity, is an important part of the body’s response to damage or pathogens. Several studies have shown that the brain can detect the state of inflammation in the body and that neurons can modulate inflammation through their activity. However, the pathways by which the brain regulates bodily inflammation are still not well understood. This week in Nature, Jin and colleagues published a study that identified: 1) specific populations of neurons that carry information about the state of inflammation in the body to the brain, and 2) specific populations of neurons in the brain that respond to this information to ramp up or dampen inflammation in the body.
How did they do it?
To cause inflammation in mice, the authors injected them with lipopolysaccharide (LPS) – a component of bacterial cell walls that is recognized by immune cells as a signal for pathogens. In response, these cells release protein messengers known as cytokines, which can be pro-inflammatory (heighten inflammation) or anti-inflammatory (reduce inflammation).
The authors then had two major goals: to determine which neurons respond to inflammation and to determine how the activity of these neurons shapes the inflammatory response.
For their first goal, the authors used imaging techniques to find out which neurons are activated after LPS, and pro- or anti-inflammatory cytokines. They then used single-cell RNA sequencing to map the genes that are expressed by these neurons, to find markers to identify them.
To manipulate the activity of neurons, the authors used the genetic technology of designer receptors exclusively activated by designer drugs or DREADDs. Depending on the type of DREADD (excitatory vs. inhibitory) inserted into cells, the authors can selectively increase or decrease the activity of sub-populations of neurons. In conjunction, the authors used another genetic technology called TRAP (targeted recombination in active populations), which allowed them to express DREADDs only in neurons that were involved in inflammation. This approach lets them manipulate the activity of inflammation-responsive neurons.
What did they find?
Using their imaging techniques, the authors found a population of neurons in the brainstem that was activated by LPS-triggered inflammation. These neurons received information about bodily inflammation from the vagus nerve. The authors found two distinct populations of vagal neurons: one responding to pro-inflammatory cytokines and expressing the genetic marker TRPA1, and the other to anti-inflammatory cytokines and expressing the genetic marker CALCA. In this way, vagal neurons transmit information regarding the inflammatory state to the brainstem.
How does manipulating the activity of these neurons affect the inflammatory response? Using DREADDs, increasing the activity of brainstem neurons was anti-inflammatory, while inhibiting their activity during LPS injection led to much higher inflammation. Similarly in the vagus nerve, increasing the activity of either the TRPA1 or the CALCA subpopulations had an anti-inflammatory effect. Remarkably, the authors further showed that in a mouse model of deadly inflammation, activating this body-brain circuit using DREADDs significantly reduced the likelihood of death.
What's the impact?
This study identified a specific body-to-brain circuit that regulates inflammation. By monitoring the levels of pro- and anti-inflammatory cytokines in the body, this circuit monitors the inflammatory response and regulates inflammation levels as needed. In the future, targeting this system may provide new strategies for treating diseases that involve dysregulation of the inflammatory response.