Plasticity of Adrenal Chromaffin Cell Function During Inflammation and Exposure to Microbe-Associated Molecular Patterns
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The sympathetic nervous system (SNS) is part of an integrative network that functions to restore homeostasis following injury and infection. The SNS provides negative feedback control over inflammation through the secretion of catecholamines from postganglionic sympathetic neurons and adrenal chromaffin cells (ACCs). Central autonomic structures receive information regarding the inflammatory status of the body and reflexively modulate SNS activity. Evidence suggests that inflammation and infection can also directly regulate ACC function. However, the precise alterations in ACC function that occur in response to regional inflammation, systemic inflammation and exposure to bacterial products have yet to be fully characterized. The present thesis was therefore performed to test the hypothesis that gastrointestinal (GI) and systemic inflammation modulate ACC Ca2+ signaling, and that ACCs possess the ability to directly detect microbe-associated molecular patterns (MAMPs). Ca2+ signaling was assessed in single ACCs isolated from control mice and mice with GI or systemic inflammation using Ca2+ imaging and perforated patch clamp electrophysiology. Acute and chronic GI inflammation consistently reduced high-K+-stimulated Ca2+ transients in ACCs through an inhibition of voltage-gated Ca2+ current. In contrast, systemic inflammation significantly enhanced high-K+-stimulated Ca2+ transients and catecholamine secretion through an increase in Ca2+ release from the endoplasmic reticulum. Incubation of control ACCs in serum obtained from mice with systemic inflammation produced a similar increase in Ca2+ signaling, suggesting that circulating mediators play an important role in this response. To determine whether ACCs can directly detect MAMPs, Ca2+ signaling, excitability and neurotransmitter release were assessed in control ACCs and ACCs incubated in media containing lipopolysaccharide (LPS). Unlike GI and systemic inflammation, LPS did not affect ACC Ca2+ signaling. However, LPS dose- and time-dependently hyperpolarized ACC resting membrane potential and enhanced large conductance Ca2+-activated K+ currents. Consistent with membrane hyperpolarization, LPS reduced ACC excitability and inhibited neuropeptide Y release. These effects were mediated by Toll-like receptor 4 and nuclear factor-κB. In summary, GI and systemic inflammation produce opposite effects on ACC Ca2+ signaling through distinct mechanisms, and ACCs can directly detect MAMPs. These findings extend our knowledge of the complex integration performed by the immune system-nervous system network during health and disease.