The Neuropeptides of Ocular Immune Privilege, α-MSH and NPY, Suppress Phagosome Maturation in Macrophages

Abstract

The ocular microenvironment has evolutionarily adapted several mechanisms of immunosuppression to minimize the induction of inflammation. Neuropeptides produced by the retinal pigment epithelial cells regulate macrophage activity. Two neuropeptides, α-melanocyte–stimulating hormone (α -MSH) and neuropeptide Y (NPY), are constitutively expressed by the retinal pigment epithelial cells. Together these two neuropeptides induce anti-inflammatory cytokine production in endotoxin-stimulated macrophages and suppress phagocytosis of unopsonized bioparticles. These neuropeptides do not suppress the phagocytosis of opsonized bioparticles; however, they do suppress phagolysosome activation or formation. In this report, we studied the possibility that α-MSH with NPY suppress phagosome maturation within macrophages using opsonized OVA-coated magnetic beads to isolate and analyze the phagosomes. The magnetic bead–containing intercellular vesicles were isolated and assayed for Rab5, Rab7, LAMP1, Iad, and OVA. The macrophages cotreated with α-MSH and NPY were suppressed in Rab7 recruitment to the phagosome with suppression in LAMP1 expression but not in Iad expression. The results demonstrated that the α-MSH/NPY cotreatment suppressed phagosome maturation. In addition, the a-MSH/NPY–cotreated macrophages were suppressed in their ability to Ag stimulate CD4+ T cell proliferation. These results imply a potential mechanism of ocular immune privilege to divert Ag processing to prevent autoreactive effector T cells from binding their target cognate Ag within the ocular microenvironment.

The Role of Retinal Pigment Epithelial Cells in Regulation of Macrophages/Microglial Cells in Retinal Immunobiology

“…The suppression is in part due to both downregulation of LAMP1, which is needed for phagolysosome acidification, and a blockade of the phagosome maturation pathway preventing the transition of phagosomes from early to intermediate (110). The suppression of phagocytosis and phagosome maturation by the RPE through the neuropeptides a-MSH and NPY would either prevent the processing of antigen within the retina or at least alter the processing of the antigen to unrecognizable amino-acid sequences that could be presented by APC in the retina (110). The RPE from eyes with autoimmune uveitis do not suppress the phagocytic pathway, and this may be associated with high levels of IL-6 expression (105).…”

Neuropeptide Y Is an Immunomodulatory Factor: Direct and Indirect

“…Besides, co-treatment of RAW264.7 macrophages with melanocyte-stimulating hormone/NPY affects lysosomal activity by inhibiting the expression of lysosomal associated membrane protein 1. This hinders the maturation of phagosomes, but does not affect their antigen presentation function ( 4 ). When treated with NPY only, the phagocytic ability of macrophages to unopsonized Escherichia coli and Staphylococcus aureus biologicals was significantly reduced.…”

“…In the peripheral nervous system, NPY is stored in the postganglionic sympathetic nerve, and co-stored and co-released with norepinephrine (NE) ( 3 ). An increasing number of studies have found widespread existence of NPY in peripheral tissues, such as the retina, smooth muscle, intestine, bone marrow, and thymus ( 4 – 7 ). Moreover, NPY is also expressed in a variety of immune cells.…”

Immunomodulatory Role of Neuropeptides in the Cornea

“…α-MSH can suppress both innate immune-mediated and adaptive immune-mediated inflammation [ 124 , 506 , 507 , 508 ]. α-MSH suppresses the production of inflammatory cytokines, ROIs, and NO in macrophages induced by endotoxin, IL-1β, and TNFα [ 502 , 509 , 510 ]. In addition, α-MSH activates suppressor cell activity in macrophages and suppresses the chemotactic activity of macrophages and neutrophils [ 69 , 511 ].…”