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Regulation and Biological Role of the Peptide/Histidine Transporter

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Regulation and Biological Role of the Peptide/Histidine Transporter Song et al. Cell Death and Disease (2018) 9:770 DOI 10.1038/s41419-018-0809-1 Cell Death & Disease ARTICLE Open Access Regulation and biological role of the peptide/histidine transporter SLC15A3 in Toll-like receptor-mediated inflammatory responses in macrophage Feifeng Song1, Yaodong Yi1,CuiLi1,YongjunHu 2, Jinhai Wang3, David E. Smith2 and Huidi Jiang1 Abstract The peptide/histidine transporter SLC15A3 is responsible for transporting histidine, certain dipeptide and peptidomimetics from inside the lysosome to cytosol. Previous studies have indicated that SLC15A3 transcripts are mainly expressed in the lymphatic system, however, its regulation and biological role in innate immune responses and inflammatory diseases are as yet unknown. In this study, mouse peritoneal macrophages (PMs), mouse bone marrow- derived macrophages (BMDMs), the human acute monocytic leukemia cell line THP-1 and the human lung epithelial carcinoma cell line A549 were used to investigate the regulation and biological role of SLC15A3 in TLR-mediated inflammatory responses. Our results showed that SLC15A3 was upregulated by TLR2, TLR4, TLR7 and TLR9 ligands in macrophages at both the mRNA and protein levels via activation of NF-κB (nuclear factor-kappa-B), MAPK (mitogen- activated protein kinase) and IRF3 (interferon regulatory factor 3). Furthermore, knockdown or overexpression of SLC15A3 influenced the TLR4-triggered expression of proinflammatory cytokines. A reporter gene assay showed that κ 1234567890():,; 1234567890():,; 1234567890():,; 1234567890():,; the SLC15A3 promotor contained potential NF- B binding sites, which were reasonable for regulating SLC15A3 by TLR-activation through NF-κB signaling. Additionally, SLC15A3 expression was increased and positively related to inflammation in mice with bacterial peritonitis. The collective findings suggest that SLC15A3 is regulated by various TLRs, and that it plays an important role in regulating TLR4-mediated inflammatory responses. Introduction respective physiological roles in the small intestine and Solute carrier (SLC) 15A3, a member of the proton- kidney have been well characterized. In contrast, coupled oligopeptide transporter (POT) family, is SLC15A3 (PHT2) and SLC15A4 (PHT1) have poor amino responsible for translocating certain dipeptide and histi- acid homology with SLC15A1 and SLC15A2 (<20%), and dine across biological membranes1. Two POT family their substrate specificity, transport kinetics, and phar- members, SLC15A1 (PEPT1) and SLC15A2 (PEPT2) macologic relevance are largely unknown. SLC15A3 is an possess around 50% amino acid identity, and their endosomal and lysosomal transporter, which is mainly – expressed in the lung, spleen and thymus1 3. Recent studies showed that SLC15A3 mRNA expression was Correspondence: Huidi Jiang ([email protected]) increased by the TLR4 (Toll-like receptor 4) agonist 1 Laboratory of Pharmaceutical Analysis and Drug Metabolism, Zhejiang lipopolysaccharide (LPS) in mouse bone marrow-derived Province Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058 Zhejiang, dendritic cells (BMDCs), and the macrophage cell lines China J774A.1 and THP-12,4. Nakamura et al. also found that 2 Department of Pharmaceutical Sciences, College of Pharmacy, University of the production of interleukin 6 (IL-6) and interleukin 1β Michigan, Ann Arbor, Michigan 48109, United States Full list of author information is available at the end of the article. (IL-1β)inSLC15A3-deficient dendritic cells was Edited by T. Kaufmann © The Author(s) 2018 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a linktotheCreativeCommons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/. Official journal of the Cell Death Differentiation Association Song et al. Cell Death and Disease (2018) 9:770 Page 2 of 15 significantly lower than wild-type cells when stimulated primary peritoneal macrophages (PMs) and bone with muramyl dipeptide (MDP), a NOD2 (nucleotide- marrow-derived macrophages (BMDMs), human acute binding oligomerization domain 2) ligand2. However, the monocytic leukemia cell line THP-1, and the human lung molecular regulatory mechanism and biological role of epithelial carcinoma cell line A549. We also investigated SLC15A3 in TLR-mediated inflammatory responses whether SLC15A3 was linked to inflammatory diseases remain poorly understood. by using a mouse model of peritonitis. Collectively, the Inflammation is a response of the innate immune sys- proposed studies will help to elucidate the molecular tem to pathogens or injury, and can be induced through regulatory mechanism of SLC15A3 in inflammatory activation of TLRs by pathogen-associated molecular responses and immune diseases, and to better understand patterns (PAMPs) such as acylated lipoproteins (TLR2 the role of SLC15A3 in immune diseases. ligand), LPS (TLR4 ligand), signal stranded RNA (ssRNA, TLR7/8 ligand) and unmethylated DNA (TLR9 ligand)5,6. Results The interaction of TLR and PAMP triggers several sig- SLC15A3 was preferentially expressed in macrophages and naling cascades that leads to the production of inflam- upregulated by TLR4 activation matory cytokines and type I interferons (IFNs)5. All TLRs On the basis of cDNA gene expression analysis, we except TLR3 can transmit signals via the myeloid differ- found that Slc15a3 was expressed at a much higher level entiation factor 88 (MyD88)-dependent pathway, which in macrophages and dendritic cells than in other mouse activate nuclear factor kappa B (NF-κB) and mitogen- peripheral blood leukocytes (Fig. 1a). To confirm this activated protein kinases (MAPKs), resulting in the result, peripheral blood mononuclear cells (PBMCs), transcription of many proinflammatory genes. TLR4 BMDCs, PMs and BMDMs were isolated from mice, also triggers the TIR domain-containing adaptor protein and Slc15a3 transcriptional levels were quantified by (TIRAP) which induces interferon β (TRIF)-dependent real-time PCR. As shown in Fig. 1b, the Slc15a3 transcript signaling and the activation of interferon regulatory fac- was present in macrophages and BMDCs, the levels of tor 3 (IRF3), thereby, resulting in IFN-α and IFN-β gene Slc15a3 were about 125-fold, 40-fold and 14-fold higher, transcription7. These TLR-induced inflammatory media- respectively, in BMDMs, PMs and BMDCs as compared tors are required for pathogen clearance, but many to PBMCs. mediators are toxic to the host and their exaggerated Macrophages play a crucial role in pathogen recognition production can further augment systemic inflammation. and the clearance of bacteria and bacterial components, It has been demonstrated that TLR-induced cytokines as they are equipped with a wide range of pattern are implicated in several autoimmune diseases, such as recognition receptors16. Since Slc15a3 is highly expressed rheumatoid arthritis, inflammatory bowel disease, and in macrophages and responsible for transporting some systemic lupus erythematosus8. Because TLR-induced bacterial components across biological membranes17,we mediators perform both protective and toxic functions, investigated whether Slc15a3 could be regulated by TLR4 it is important to better understand the TLR signaling activation. As shown in Fig. 1c, d, Slc15a3 was sig- pathway and to dampen the production of proin- nificantly upregulated in LPS-treated mouse PMs and flammatory mediators. BMDMs at both the mRNA and protein levels. SLC15A4, another POT family member, is also localized in endosomes and lysosomes, and has similar transport SLC15A3 was upregulated by activation of NF-κB and the properties with SLC15A39,10. Several studies have repor- promoter region of SLC15A3 contained NF-κB binding ted that SLC15A4 is closely associated with inflammatory sites diseases such as diabetes, systemic lupus erythematosus Because LPS activates TLR4 and subsequently leads to – and inflammatory bowel disease11 14.InSLC15A4-defi- the activation of NF-κB, we next determined whether NF- cient plasmacytoid dendritic cells (pDCs), TLR7 and κB activation was required for the LPS-induced upregu- TLR9-induced type I IFNs and proinflammatory cytokines lation of Slc15a3 in mouse PMs and BMDMs. As shown production were abrogated13,15. Studies have reported in Fig. 2a, b, the upregulation of Slc15a3 was abolished by that SLC15A4 is essential for signaling through TLR7 and the specific NF-κB inhibitor BAY 11–7082. Moreover, TLR9, but it is unclear whether SLC15A3 also has a role TLR4 signaling induced the transcription of Il-6 and Tnf- in TLR7 and TLR9 signaling. Currently, both SLC15A4 α, which were also reduced by BAY 11–7082 (Supple- and TLRs are associated with some inflammatory dis- mentary Figure S1). The expression changes of Slc15a3 eases, but limited information is available concerning the displayed in a similar trend as proinflammatory cytokines relationship
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