Neuropeptide Y Negatively Influences Monocyte Recruitment to the Central Nervous System during Retrovirus Infection

Abstract

Monocyte infiltration into the CNS is a hallmark of several viral infections of the central nervous system (CNS), including retrovirus infection.Understanding the factors that mediate monocyte migration in the CNS is essential for the development of therapeutics that can alter the disease process. In the current study, we found that neuropeptide Y (NPY) suppressed monocyte recruitment to the CNS in a mouse model of polytropic retrovirus infection. NPY ؊/؊ mice had increased incidence and kinetics of retrovirus-induced neurological disease, which correlated with a significant increase in monocytes in the CNS compared to wildtype mice. Both Ly6C hi inflammatory and Ly6C lo alternatively activated monocytes were increased in the CNS of NPY ؊/؊ mice following virus infection, suggesting that NPY suppresses the infiltration of both cell types. Ex vivo analysis of myeloid cells from brain tissue demonstrated that infiltrating monocytes expressed high levels of the NPY receptor Y2R. Correlating with the expression of Y2R on monocytes, treatment of NPY ؊/؊ mice with a truncated, Y2R-specific NPY peptide suppressed the incidence of retrovirus-induced neurological disease. These data demonstrate a clear role for NPY as a negative regulator of monocyte recruitment into the CNS and provide a new mechanism for suppression of retrovirus-induced neurological disease. IMPORTANCEMonocyte recruitment to the brain is associated with multiple neurological diseases. However, the factors that influence the recruitment of these cells to the brain are still not well understood. In the current study, we found that neuropeptide Y, a protein produced by neurons, affected monocyte recruitment to the brain during retrovirus infection. We show that mice deficient in NPY have increased influx of monocytes into the brain and that this increase in monocytes correlates with neurological-disease development. These studies provide a mechanism by which the nervous system, through the production of NPY, can suppress monocyte trafficking to the brain and reduce retrovirus-induced neurological disease. The recruitment of monocytes into the central nervous system (CNS) is associated with a number of neurological diseases. Monocyte recruitment to the CNS has been reported for traumatic brain injury (TBI), misfolded-protein diseases, and multiple sclerosis (MS), as well as many different viral infections, including West Nile virus (WNV), herpes simplex virus (HSV), and retroviruses, such as HIV (1-4). Monocyte trafficking is particularly important for retrovirus-induced neurological diseases, as monocytes are susceptible to retrovirus infection (5, 6).Monocytes recruited to the CNS may contribute to pathogenesis in these neurological diseases. Decreased cognitive performance correlated with increased monocyte infiltration in HIVassociated neurocognitive disorders (HAND) (1). Additionally, infiltration of monocytes was found to be important for seizure development in a mouse model of Theiler's murine encephalitis (7). Recent studies in a mouse mo...

Genetic Association with Subgingival Bacterial Colonization in Chronic Periodontitis

“…Additional evidence that NPY could be involved in the maintenance of host-microbe homeostasis at the periodontium derives from the observation that NPY levels are higher in human gingival crevicular fluid in healthy conditions when compared to periodontitis [ 71 ]. Additionally, recent evidence has demonstrated immune modulatory functions for NPY, inhibiting the recruitment of monocytes in severe infections of the central nervous system [ 72 ]. Similarly, in vivo experiments suggest that NPY agonists are effective in diminishing the blood title of TNFα in endotoxin-induced septic shock [ 73 ].…”

Cellular prion protein is present in mitochondria of healthy mice

“…Formalin fixed and paraffin embedded sagittal sections of mouse brain (5 microns) were deparaffinized and rehydrated followed by antigen retrieval and blocking as described previously 85 . All subsequent manipulations were done at room temperature unless otherwise indicated.…”

“…Sections were incubated for 1 hr with a rabbit polyclonal COXIV antibody diluted 1:100 in 1X phosphate buffered saline (PBS)/1% donkey serum (DS, Invitrogen) followed by 2 × 10 min rinses in 1X PBS/0.05% fish skin gelatin (FSG, Sigma-Aldrich). Slides were then incubated in goat anti-rabbit IgG conjugated to AlexaFluor 488 antibody diluted 1: 500 in 1X PBS/1% DS for 1 hour, rinsed 2 × 10 mins in 1X PBS/0.05% FSG and blocked as described previously 85 . Slides were then incubated at 4 °C overnight with the mouse monoclonal antibody 3F4 conjugated to biotin (1:50 dilution), rinsed 2 × 10 mins, incubated with a 1:500 dilution of streptavidin conjugated to AlexaFluor 594, and rinsed again for 2 × 10 mins as described above.…”

Neuropeptide Y Is an Immunomodulatory Factor: Direct and Indirect

“…Moreover, NPY inhibited the recruitment of retroviral-infected monocytes to CNS. This process is linked to the upregulation of monocyte Y2R ( 72 ). Indeed, NPY enhances the adhesion of monocytes through Y2R ( 36 ).…”