RESUMEN
Secreted by activated cells or passively released by damaged cells, extracellular HMGB1 is a prototypical damage-associated molecular pattern (DAMP) inflammatory mediator. During the course of developing extracorporeal approaches to treating injury and infection, we inadvertently discovered that haptoglobin, the acute phase protein that binds extracellular hemoglobin and targets cellular uptake through CD163, also binds HMGB1. Haptoglobin-HMGB1 complexes elicit the production of antiinflammatory enzymes (heme oxygenase-1) and cytokines (e.g., IL-10) in WT but not in CD163-deficient macrophages. Genetic disruption of haptoglobin or CD163 expression significantly enhances mortality rates in standardized models of intra-abdominal sepsis in mice. Administration of haptoglobin to WT and to haptoglobin gene-deficient animals confers significant protection. These findings reveal a mechanism for haptoglobin modulation of the inflammatory action of HMGB1, with significant implications for developing experimental strategies targeting HMGB1-dependent inflammatory diseases.
RESUMEN
The axons of the sensory, or afferent, vagus nerve transmit action potentials to the central nervous system in response to changes in the body's metabolic and physiological status. Recent advances in identifying neural circuits that regulate immune responses to infection, inflammation and injury have revealed that vagus nerve signals regulate the release of cytokines and other factors produced by macrophages. Here we record compound action potentials in the cervical vagus nerve of adult mice and reveal the specific activity that occurs following administration of the proinflammatory cytokines tumor necrosis factor (TNF) and interleukin 1ß (IL-1ß). Importantly, the afferent vagus neurograms generated by TNF exposure are abolished in double knockout mice lacking TNF receptors 1 and 2 (TNF-R1/2KO), whereas IL-1ß-specific neurograms are eliminated in knockout mice lacking IL-1ß receptor (IL-1RKO). Conversely, TNF neurograms are preserved in IL-1RKO mice, and IL-1ß neurograms are unchanged in TNF-R1/2KO mice. Analysis of the temporal dynamics and power spectral characteristics of afferent vagus neurograms for TNF and IL-1ß reveals cytokine-selective signals. The nodose ganglion contains the cell bodies of the sensory neurons whose axons run through the vagus nerve. The nodose neurons express receptors for TNF and IL-1ß, and we show that exposing them to TNF and IL-1ß significantly stimulates their calcium uptake. Together these results indicate that afferent vagus signals in response to cytokines provide a basic model of nervous system sensing of immune responses.
