Abstract
In the immune system, neuropilins (NRPs), including NRP-1 and NRP-2, are expressed in thymocytes, dendritic cells, regulatory T cells and macrophages. Their functions on immune cells around the neoplastic cells vary into pro-angiogenesis, tumor progression and anti-angiogenesis according to their ligands. Even though NRPs expression on malignant tumors and immune system has studied, a PubMed-based literature query did not yield any articles describing NRPs expression on tissue-specific macrophages. The aims of this study were (i) to detect NRPs expression on tissue-specific macrophages in the brain, liver, spleen, lymph node and lung; (ii) to observe NRPs expression in classes of macrophages, including alveolar macrophages (AMs), bronchial macrophages (BMs), interstitial macrophages (IMs), intravascular macrophages (IVMs) and macrophage subsets (M1, M2 and Mox) in lung; and (iii) to detect the co-expression of NRPs and dendritic cell-specific ICAM-3-grabbing nonintegrin (DC-SIGN) in AMs. Both NRPs were specifically detected in AMs among tissue-specific macrophages by immunohistochemistry (IHC). NRPs mRNA expression levels were characterized in normal lung by reverse transcriptase polymerase chain reaction (RT-PCR) and in situ-polymerase chain reaction (in situ-PCR). The expression of both NRPs was detected in AMs, BMs and IVMs by IHC. The frequency of NRPs+ AMs in lung tissue adjacent to the cancer margin was significantly higher than the frequencies in inflamed and normal lung tissue. Double and triple IHC demonstrated that NRPs are expressed on all macrophage subsets in lung. Double IHC showed co-expression of DC-SIGN and NRPs in AMs. This study demonstrated for the first time the specific expression of both NRPs in AMs among tissue-specific macrophages and their expression on M1, M2 and Mox macrophages. Furthermore, the possible origin of AMs from blood monocytes could be suggested from a co-expression of NRPs and DC-SIGN.
Highlights
Neuropilins (NRPs) are 120–130 kDa transmembrane non-tyrosine kinase glycoproteins, identified as co-receptors for semaphorin (SEMA) and vascular endothelial growth factor (VEGF)
The c- and transmembrane domains are involved in receptor dimerization, a requirement of SEMA 3A signaling, with the c-domain thought to play a role in NRP-1 oligomerization
NRP-1 and NRP-2 were expressed in alveolar macrophages (AMs) among tissue-specific macrophages (Figs 1 and 2)
Summary
Neuropilins (NRPs) are 120–130 kDa transmembrane non-tyrosine kinase glycoproteins, identified as co-receptors for semaphorin (SEMA) and vascular endothelial growth factor (VEGF). Detection analysis of the domains suggests that the a1/a2 and b1/b2 domains are involved in class 3 SEMA functioning as receptors for neuronal guidance and the b1/b2 is involved in the binding of VEGF165. A neuropilin interacting protein (NIP or synectin) containing cytoplasmic PDZ (PSD-95/Dlg/ZO-1)-domain has been identified and its domain is responsible for interaction with VEGFR-2 [3]. Both classes of NRPs control endothelial cell behavior. It is known that NRPs bind to members of the fibroblast growth factor family, along with galectin, hepatocyte growth factor/scatter factor, anti-thrombin III, prion protein, transforming growth factor-β and platelet-derived growth factor [4,5,6,7,8]
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