PACAP protects against TNFα-induced cell death in olfactory epithelium and olfactory placodal cell lines

Abstract

In mouse olfactory epithelium (OE), pituitary adenylate cyclase activating peptide (PACAP) protects against axotomy-induced apoptosis. We used mouse OE to determine whether PACAP protects neurons during exposure to the inflammatory cytokine TNFα. Live slices of neonatal mouse OE were treated with 40 ng/ml TNFα ± 40 nM PACAP for 6 hours and dying cells were live-labeled with 0.5% propidium iodide. TNFα significantly increased the percentage of dying cells while coincubation with PACAP prevented cell death. PACAP also prevented TNFα-mediated cell death in the olfactory placodal (OP) cell lines, OP6 and OP27. Although OP cell lines express all three PACAP receptors (PAC1, VPAC1,VPAC2), PACAP's protection of these cells from TNFα was mimicked by the specific PAC1 receptor agonist maxadilan and abolished by the PAC1 antagonist PACAP6-38. Treatment of OP cell lines with blockers or activators of the PLC and AC/MAPKK pathways revealed that PACAP-mediated protection from TNFα involved both pathways. PACAP may therefore function through PAC1 receptors to protect neurons from cell death during inflammatory cytokine release in vivo as would occur upon viral infection or allergic rhinitis-associated injury.

Olfactory and middle meatal cytokine levels correlate with olfactory function in chronic rhinosinusitis

“…14 Inflammation in CRS is mediated largely by proinflammatory cytokines that circulate locally in sinonasal tissue. Several cytokines have neurotoxic potential, [16][17][18][19] and it is conceivable that the olfactory dysfunction in CRS patients may be mediated in part by their effects on olfactory neuronal cell function, apoptosis, differentiation, and proliferation. Recent evidence from transgenic mouse models have supported this olfactory inflammation hypothesis, with local overexpression of proinflammatory cytokines such as tumor necrosis factor-a (TNF-a) and interferon-c, resulting in inhibition of olfactory neuron function, turnover, or survival.…”

Pituitary adenylate cyclase activating peptide-27 – like immunoreactive nerve fibers in the mucosal layer of canine gastrointestinal tract in physiology and during inflammatory bowel disease

“…It is also known that PACAP (mainly via PAC1 receptor) affects proliferation of neurons, axon regeneration, and development of the nervous system (3). It also plays an important role in the protection of non-neuronal tissues, such as the heart, kidneys, or olfactory epithelium, where it protects cells against inflammatory cytokine TNFα -inducing cell death (18,19,30). These facts, with an increase in PACAP-27-like immunoreactivity in the enteric nervous system after axotomy observed in previous studies (14), suggest that this peptide also plays a neuroprotective role in the ENS.…”

Olfactory epithelium changes in germfree mice

“…Renewal of the OE throughout life has been linked to its aggressive surrounding environment 11 . Among potential threats, microorganisms could release toxins or trigger inflammation, thus promoting apoptosis 17 . We thus examined whether the cellular turn-over was altered in germfree animals.…”

“…They were euthanised by decapitation following sodium pentobarbital anaesthesia and heads were removed to perform OE analyses. Procedures were carried out in accordance with the European guidelines for the care and use of laboratory animals; they were approved by the Ethics Committee of AgroParisTech and the INRA Research Center of Jouy-en-Josas (approval reference: 14 , 15 , 16 , 17 , 18 , 19 , 20 , 21 , 22 , 23 , 24 , 25 , 26 , 27 , 28 , 29 , 30 , 31 , 32 , 33 , 34 , 35 , 36 , 37 , 38 , 39 , 40 , 41 , 42 ).…”