Neurokinin-1 Receptor Expression and Function in Human Macrophages and Brain Perspective on the Role in HIV Neuropathogenesis Steven D. Douglas, a Jian-Ping Lai, a Florin Tuluc, a Lynnae Schwartz, b and Laurie E. Kilpatrick a a Division of Allergy and Immunology, Joseph Stokes Jr. Research Institute at the Children’s Hospital of Philadelphia, Department of Pediatrics, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, USA b Department of Anesthesia and Critical Care Medicine, Joseph Stokes Jr. Research Institute at the Children’s Hospital of Philadelphia, Department of Pediatrics, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, USA Substance P (SP) is upregulated in HIV infection in adult men and women, as deter- mined by increased plasma levels. There is a reciprocal and bidirectional relationship between substance P and HIV in HIV-infected monocyte-derived macrophages and cell lines (e.g., THP-1). Substance P up-regulates HIV and HIV up-regulates SP protei expression. Neurokinin-1 receptor (NK1R) antagonists inhibit HIV infectivity through downregulation of the chemokine receptor, CCR5,and downregulation of HIV LTR. Neurokinin-1 receptor is expressed in full-length and truncated forms. The full-length NK1R is capable of signaling, whereas the truncated NK1R primes the chemokine rec tor CCR5. Both full-length and truncated NK1R are expressed in several brain regions in human autopsy brains. SP–NK1R interactions have regulatory roles in inflamma- tion and infection. The differential expression of truncated and full-length NK1R has important biological consequences. These include receptor–receptor interaction (e.g. NK1R–CCR5); changes in expression during cell differentiation (e.g., THP-1 cells); and differences in regional tissue distribution (e.g., differences in different brain regions NK1R-SP receptor pathways are important cell regulatory pathways. Key words: neurokinin-1 receptor; substance P; HIV/AIDS; brain; macrophages Introduction The interaction between neurokinin-1 re- ceptor (NK1R) and its preferred ligand, sub- stance P (SP), leadsto important functional consequences in the immune and nervous sys- tem. We have demonstrated a bidirectional in- teraction between NK1R and its ligand, SP, and the CCR5 receptor and itsinteraction with its preferring ligand (CCL5). 1 –3 A specific NK1R antagonist(CP96,345) inhibits HIV Address for correspondence: Steven D. Douglas, M.D., Professor and Associate Chair, Pediatrics, Division ofAllergy and Immunology, The Children’s Hospital of Philadelphia, 34th & Civic Center Blvd., Philadel- phia, PA 19104. DOUGLAS@email.chop.edu entry into monocyte-derived macrophages by downregulating CCR5. 3 Using a macrophage cell line (THP-1), we discovered that with differentiation of human peripheral blood– derived monocyte-to-macrophages, there is e pression of both the full-length and truncated forms ofNK1R. 4 In autopsy brain samples, we have recently observed differential expres- sion of the full-length and truncated forms of NK1R. 5,6 Tachykinins The mammalian tachykinins (TAC), also termed neurokinins, are a family of peptides Ann. N.Y. Acad. Sci. 1144: 90–96 (2008). C 2008 New York Academy of Sciences. doi: 10.1196/annals.1418.007 90