AUTHOR=Shah Ashti M. , Zamora Ruben , Barclay Derek , Yin Jinling , El-Dehaibi Fayten , Addorisio Meghan , Tsaava Tea , Tynan Aisling , Tracey Kevin , Chavan Sangeeta S. , Vodovotz Yoram 

TITLE=Computational inference of chemokine-mediated roles for the vagus nerve in modulating intra- and inter-tissue inflammation

JOURNAL=Frontiers in Systems Biology

VOLUME=4

YEAR=2024

URL=https://www.frontiersin.org/journals/systems-biology/articles/10.3389/fsysb.2024.1266279

DOI=10.3389/fsysb.2024.1266279

ISSN=2674-0702

ABSTRACT=<p><bold>Introduction:</bold> The vagus nerve innervates multiple organs, but its role in regulating cross-tissue spread of inflammation is as yet unclear. We hypothesized that the vagus nerve may regulate cross-tissue inflammation via modulation of the putatively neurally regulated chemokine IP-10/CXCL10.</p><p><bold>Methods:</bold> Rate-of-change analysis, dynamic network analysis, and dynamic hypergraphs were used to model intra- and inter-tissue trends, respectively, in inflammatory mediators from mice that underwent either vagotomy or sham surgery.</p><p><bold>Results:</bold> This analysis suggested that vagotomy primarily disrupts the cross-tissue attenuation of inflammatory networks involving IP-10 as well as the chemokines MIG/CXCL9 and CCL2/MCP-1 along with the cytokines IFN-γ and IL-6. Computational analysis also suggested that the vagus-dependent rate of expression of IP-10 and MIG/CXCL9 in the spleen impacts the trajectory of chemokine expression in other tissues. Perturbation of this complex system with bacterial lipopolysaccharide (LPS) revealed a vagally regulated role for MIG in the heart. Further, LPS-stimulated expression of IP-10 was inferred to be vagus-independent across all tissues examined while reducing connectivity to IL-6 and MCP-1, a hypothesis supported by Boolean network modeling.</p><p><bold>Discussion:</bold> Together, these studies define novel spatiotemporal dimensions of vagus-regulated acute inflammation.</p>