PACAP Regulator Treg Abundance

PACAP as an Intrinsic Regulator of Treg Abundance

PACAP – Treg Abundance

A study published in the Proceedings of the National Academy of Sciences of the United States of America (PNAS) provides perhaps the first evidence that endogenous pituitary adenylyl cyclase-activating polypeptide (PACAP) modulates the production or expansion of regulatory T cells (Treg) and T helper (Th)17 lymphocytes.

PACAP is a 38-amino-acid neuropeptide identified in 1989 from an ovine hypothalamic extract on the basis of its ability to stimulate cAMP formation in anterior pituitary cells. The pituitary adenylyl cyclase-activating polypeptide belongs to the vasoactive intestinal polypeptide (VIP)-secretin-growth hormone-releasing hormone-glucagon superfamily. Thus, its closest family member is vasoactive intestinal peptide (VIP). One of its effects is to stimulate enterochromaffin-like cells. It binds to vasoactive intestinal peptide receptor and to the pituitary adenylate cyclase-activating polypeptide receptor.

The pituitary adenylyl cyclase-activating polypeptide is widely distributed in the brain and peripheral organs, particularly the endocrine pancreas, gonads, respiratory and urogenital tracts, and it is capable of eliciting a broad spectrum of biological actions. Its actions within hypothalamic, limbic, and mnemonic systems underlie its roles in stress regulation, affective processing, neuroprotection, and cognition.

The most abundant population of PACAP-containing neurons and the highest density of PACAP binding sites are found in the hypothalamus. In particular, a dense accumulation of pituitary adenylyl cyclase-activating polypeptide-immunoreactive neurons and pituitary adenylyl cyclase-activating polypeptide receptors are present in the magnocellular region of the PVN and SON, where the neurosecretory perikarya producing oxytocin and vasopressin are located.

Intracerebroventricular and intracisternal injections of pituitary adenylyl cyclase-activating polypeptide induce a dose-dependent elevation of plasma vasopressin. In the neural lobe of the pituitary, pituitary adenylyl cyclase-activating polypeptide stimulates the release of oxytocin and vasopressin through the activation of the cAMP/PKA signaling pathway. Collectively, these observations indicate that pituitary adenylyl cyclase-activating polypeptide is a potent activator of hypothalamic magnocellular neurons.

PACAP is classically viewed as a neurotransmitter, and is co-stored with acetylcholine in the splanchnic nerve terminals innervating the adrenal medulla. In the adrenal medulla, pituitary adenylyl cyclase-activating polypeptide is released only at high frequencies of stimulation, contributing to the regulation of epinephrine (adrenaline) secretion, and apparently in the stress signaling at the splanchnic–adrenal synapse.

However, the role of endogenously produced pituitary adenylyl cyclase-activating polypeptide in immune system homeostasis is poorly understood. Research in the early 1980s implicated VIP as a regulator of immune function. VIP can modulate both innate and adaptive immunity, showing a predominant anti-inflammatory action on macrophages, promoting a positive Th2/Th1 cytokine balance, and enhancing the production of regulatory T cells (Tregs).

Later it was found that pituitary adenylyl cyclase-activating polypeptide could mimic many of these actions, suggesting the involvement of VPAC receptors. Moreover, it was determined that both VIP and pituitary adenylyl cyclase-activating polypeptide  are expressed in lymphocytes and other immune cell types. Importantly, recent evidence indicates that VPAC receptors may be promising targets for the treatment of inflammatory diseases, and in particular, Th1-associated pathologies such as MS and rheumatoid arthritis.

In the PNAS study, Yossan-Var Tan and colleagues from the David Geffen School of Medicine, University of California, Los Angeles, CA, USA used PACAP-deficient (KO) mice and the MOG35–55 EAE model to study the potential actions of endogenous pituitary adenylyl cyclase-activating polypeptide.

The authors found that the PACAP-deficient mice developed an enhanced experimental autoimmune encephalomyelitis (EAE) when compared to control animals, and with heightened clinical severity, increased mortality, and a delayed and diminished recovery phase.

This was associated with enhanced Th1 and Th17 immune responses, diminished Th2 activity in the CNS and lymph nodes, and a reduction of Treg abundance in the lymph nodes.

The decrease in Treg abundance may be particularly important in explaining the increased severity of EAE and delayed recovery in pituitary adenylyl cyclase-activating polypeptide KO mice. Consistent with a reduction in Treg abundance, enhanced proliferation and increased Th1/Th17 cytokine production were observed in MOG-stimulated cultures of immunized PACAP KO mice.

Based on previous research PACAP is believed to exert anti-inflammatory effects by inhibiting macrophage activity and inducing a Th2 shift. The PNAS study, however is probably the first to demonstrate PACAP’s immunoregulatory effects on Treg and Th17 lymphocytes. Thus, the study identifies pituitary adenylyl cyclase-activating polypeptide as one of the few known intrinsic regulators of Treg function and production. Overall, PACAP appears to be an important endogenous immunomodulatory molecule with protective actions in a well-established autoimmune disease model.

Source: Proc Natl Acad Sci USA 2009, 106:2012
Read more: PNAS

Image Credit (Left panel): Pituitary Adenylate Cyclase Activating Peptide (PACAP) binds to three G-protein coupled receptors (GPCRs): PACAP binds to three GPCRs: VPAC1, VPAC2, and PAC1. PAC1 is specifically selective for PACAP27 and PACAP38, binding with high affinity. Once bound to its associated GPCRs, PACAP activates Gs or Gq subunits. This activation leads to the initiation of adenylate cyclase activity to stimulate the conversion of ATP to cAMP or the initiation of phospholipase C activity to stimulate protein kinase C. Adapted from Rubio-Beltrán et al.: From Pituitary Adenylate Cyclase Activating Peptide and Post-traumatic Stress Disorder: From Bench to Bedside, by Manessa Riser and Seth Davin Norrholm.

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