Pituitary adenylyl cyclase-activating polypeptide is an intrinsic regulator of Treg abundance and protects against experimental autoimmune encephalomyelitis.
Pituitary adenylyl cyclase-activating polypeptide (PACAP) is a widely expressed neuropeptide originally discovered in the hypothalamus. It closely resembles vasoactive intestinal peptide (VIP), a neuropeptide well known to inhibit macrophage activity, promote Th2-type responses, and enhance regulatory T cell (Treg) production. Recent studies have shown that administration of PACAP, like VIP, can attenuate dramatically the clinical and pathological features of murine models of autoimmune diseases such as experimental autoimmune encephalomyelitis (EAE) and collagen-induced arthritis. However, specific roles (if any) of endogenous VIP and PACAP in the protection against autoimmune diseases have not been explored. Here, we subjected PACAP-deficient mice to myelin oligodendrocyte glycoprotein (MOG(35-55))-induced EAE. MOG immunization of PACAP-deficient mice triggered heightened clinical and pathological manifestations of EAE compared to wild-type mice. The increased sensitivity was accompanied by enhanced mRNA expression of proinflammatory cytokines (TNFalpha, IL-6, IFN-gamma, IL-12p35, IL-23p19, and IL-17), chemokines (MCP-1/CCL2, MIP-1alpha/CCL3, and RANTES/CCL5), and chemotactic factor receptors (CCR1, CCR2, and CCR5), but downregulation of the anti-inflammatory cytokines (IL-4, IL-10, and TGF-beta) in the spinal cord. Moreover, the abundance of CD4(+)CD25(+)FoxP3(+) Tregs in lymph nodes and levels of FoxP3 mRNA in the spinal cord were also diminished. The reduction in Tregs was associated with increased proliferation and decreased TGF-beta secretion in lymph node cultures stimulated with MOG. These results demonstrate that endogenous PACAP provides protection in EAE and identify PACAP as an intrinsic regulator of Treg abundance after inflammation.
Tan
Yossan-Var
YV
Semel Institute/Department of Psychiatry, David Geffen School of Medicine, University of California, Los Angeles, CA 90095, USA.
Abad
Catalina
C
Lopez
Robert
R
Dong
Hongmei
H
Liu
Shen
S
Lee
Alice
A
Gomariz
Rosa P
RP
Leceta
Javier
J
Waschek
James A
JA
D000818:Animals; D001327:Autoimmune Diseases / Q000209:etiology; D016207:Cytokines / Q000235:genetics; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000139:chemically induced / Q000209:etiology*; D005786:Gene Expression Regulation / Q000276:immunology; D008198:Lymph Nodes / Q000276:immunology; D018655:Lymphocyte Count; D051379:Mice; D018345:Mice, Knockout; D009185:Myelin Proteins; D018992:Myelin-Associated Glycoprotein; D063308:Myelin-Oligodendrocyte Glycoprotein; D051219:Pituitary Adenylate Cyclase-Activating Polypeptide / Q000172:deficiency / Q000502:physiology*; D054388:Receptors, CCR / Q000235:genetics; D013116:Spinal Cord / Q000378:metabolism; D050378:T-Lymphocytes, Regulatory / Q000473:pathology*; D014660:Vasoactive Intestinal Peptide / Q000502:physiology
C495402:Adcyap1 protein, mouse; D016207:Cytokines; C571327:Mog protein, mouse; D009185:Myelin Proteins; D018992:Myelin-Associated Glycoprotein; D063308:Myelin-Oligodendrocyte Glycoprotein; D051219:Pituitary Adenylate Cyclase-Activating Polypeptide; D054388:Receptors, CCR; D014660:Vasoactive Intestinal Peptide