The autonomic nervous system (ANS) plays a critical role in regulating lung function, but how pulmonary inflammation influences ANS activity remains poorly understood. Furthermore, it is unclear whether such inflammatory episodes have lasting effects on respiratory physiology and local immune responses. Recent work has identified a subset of neurons in the Nucleus Tractus Solitarius (NTS) capable of sensing airway allergic inflammation and modulating bronchoconstriction via a noradrenergic feedback pathway (Sun et al., Nature 2024). In the gut, region-specific encoding of immune challenges in the brain has already been demonstrated (Koren et al., Cell 2021). Whether a similar brain-immune communication exists in the lungs in response to bacterial inflammation remains an open question. Here, we investigate whether a bacterial lung challenge can be detected and encoded by specific brain regions, and whether this encoding subsequently influences pulmonary immune function. To do so, we use a model of Acute Lung Inflammatory Syndrome (ALIS) induced by intratracheal administration of lipopolysaccharide (LPS). We map neuronal activity across the brain using c-Fos immunostaining, with a focus on the NTS. We then used the combination of c-Fos-CreERT2 mouse line with stereotaxic injection of AAVs expressing the hM3D(Gq) receptor (a Designer Receptor Exclusively Activated by Designer Drug [DREADDs]) to pharmacogenetically manipulate NTS neurons previously activated by LPS (trapped neurons). Measuring local immune response, plethysmography and mapping of brain neurons activity, we show that upon activation, we retrieve the changes in breathing activity observed during LPS challenges. Our data suggest that LPS-induced lung inflammation is encoded in specific brain regions and that these neuronal ensembles contribute to a feedback loop modulating respiratory function.
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