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Recently, there has been the realization that neurobiology and inflammatory signaling are intimately interrelated with one another; however, this field remains in its infancy. Many studies that have sought to elucidate the role of the autonomic nervous system in neural modulation of the inflammatory response have used various models of septic shock. For example, it has been seen that when macrophages are stimulated with LPS in vitro, the addition of acetylcholine, the principle vagal neurotransmitter, significantly attenuates the release of inflammatory cytokines, but not the anti-inflammatory cytokine interleukin (IL)-10.1 In vivo, intact vagal signaling has been shown to be necessary to activate the cholinergic anti-inflammatory pathway, leading to decreased proinflammatory cytokine expression after endotoxin-induced shock.2 Thus, a physiologic connection between the nervous and innate immune systems has been confirmed, with potential for therapeutic exploitation.

In this issue of HEPATOLOGY, Ji et al.3 investigate the role of the neuropeptide pituitary adenylate cyclase-activating polypeptide (PACAP) and its receptors in warm hepatic ischemia/reperfusion (I/R). PACAP is not only expressed throughout the nervous system, but also in the adrenal gland, gastrointestinal tract, pancreas, and liver.4 PACAP is capable of binding several G protein–coupled receptors that are found on immune cells such as lymphocytes and macrophages, in addition to hepatocytes.4 Ji et al. determined that both endogenous levels of PACAP increased after I/R, peaking at 12-24 hours after reperfusion, in addition to expression of all known receptors for PACAP.3 Interestingly, a protective role of PACAP was found, with mice deficient in functional PACAP having a significantly increased susceptibility to IR (wild-type versus knockout; 4,680 ± 554 versus 31,172 ± 6,994 IU/L).3 Confirming this finding, the addition of exogenous PACAP led to significant protection as seem by ALT levels and liver histology.3 Furthermore, exogenous administration of PACAP decreased neutrophil and macrophage infiltration, decreased inflammatory cytokine and chemokine expression, increased IL-10 levels, and decreased apoptosis.3 Mechanistically, PACAP was shown to increase cyclic adenosine monophosphate levels and protein kinase A activity, with the hepatoprotective effects of PACAP negated by addition of H-89, a protein kinase A inhibitor.31

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Figure 1. Schematic overview of hepatic ischemia-reperfusion. Simplified illustration demonstrating several critical factors regulating hepatic IR. Ischemia-reperfusion leads to many simultaneous homeostatic perturbances including the release of DAMPs, which may activate PRR, such as TLRs and NLRs, with ultimate upregulation of proinflammatory mediators. Ji et al.3 describe a mechanism for balancing this response, with the neuropeptide PACAP decreasing hepatic injury by the down-regulation of inflammatory mediators. Alternatively, it has been shown that the autonomic nervous system may also downregulate the innate inflammatory response via the vagal inputs.11 The relationship between PACAP and the autonomic nervous response has yet to be elucidated. AP-1, activator protein 1; ATP, adenosine triphosphate; Casp-1, caspase-1; DAMP, damage-associated molecular pattern molecules; IL-1β, interleukin-1β; IRF-3, interferon regulatory factor 3; MAPK, mitogen-associated protein kinase; MPT, mitochondrial permeability transition; NF-κB, nuclear factor κB; NK, natural killer; NLR, NOD-like receptors; PACAP, pituitary adenylate cyclase-activating polypeptides; PKA, protein kinase A; PMN, polymorphonuclear neutrophils; PRR, pattern recognition receptors; ROS, reactive oxygen species; TLR, Toll-like receptors.

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The work by Ji et al. describes the novel role of a neuropeptide in hepatic I/R and provides us with a new therapeutic avenue to potentially abrogate the sterile inflammatory response after I/R. I/R is a process whereby an initial hypoxic insult and subsequent return of blood flow leads to the propagation of innate immune responses with resultant tissue damage and possible organ dysfunction. Hepatic I/R is a clinically relevant condition that may occur not only in the setting of organ transplantation and elective liver resection but also with episodes of global hypoperfusion, such as hemorrhagic shock. Damage related to the initial ischemic insult and the early phases of reperfusion are secondary to reactive oxygen species generation, decreased adenosine triphosphate production, and increased mitochondrial permeability transition.5, 6 However, after the initial insult, I/R is perpetuated by an innate immune response. This response is mediated not only by the classical proinflammatory cytokines, such as tumor necrosis factor-α and IL-1β, but also by the recently described endogenous danger signals or damage-associated molecular pattern (DAMP) molecules. Examples of DAMP molecules that lead to increased inflammation include the canonical DAMP, HMGB1, in addition to more recently described molecules such as histones.6, 7 Additionally, pattern recognition receptors have been shown to be necessary for the I/R-associated innate immune response. Pattern recognition receptors such as TLR4, TLR9, and NALP3 have all been shown to be key components in I/R-associated injury, with significant protection afforded to mice that lack these receptors.7-10 The activation of the innate immune response via PRRs leads to the expression of chemokines and intercellular adhesion molecules with the subsequent infiltration of neutrophils and other inflammatory cells into the liver, resulting in further I/R-associated injury. The study by Ji et al. is the first to demonstrate the role of an intrinsic neuropeptide in maintaining hepatic homeostasis in inflammation and organ damage following liver I/R. The use of PACAP to regulate immune responses and activate cytoprotective mechanisms should be investigated further as a novel therapy to manage liver inflammation associated with I/R.

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