Dipeptidyl Peptidase 4 Inhibitors and Immune Modulatory Functions PDF

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journal homepage: Dipeptidyl peptidase 4 inhibitors and their potential immune modulatory functions Shiying Shao a, QinQin Xu a, Xuefeng Yu a, Ruping Pan b, Yong a Division of Endocrinology, Department of Internal Medicine, b Department of Nuclear Medicine, Tongji hospital, Tongji a r t i c l e i n f o Available online 14 February 2020 Keywords: Dipeptidyl peptidase 4 Cluster of differentiation 26 Type 2 diabetes mellitus Immunotherapy Contents 1. Introduction............................. 2. Effect of DPP4/CD26 on the immune 3. Effects and underlying mechanisms 4. Outlook.................................. Acknowledgments............................... References.................................... 1. Introduction Dipeptidyl peptidase 4 (DPP4) is a transmembrane glycoprotein with a molecular mass of 220–240 kDa, originally known as T cell surface marker cluster of differentiation 26 (CD26) (Kameoka, Tanaka, Nojima, Schlossman, & Morimoto, 1993; Ohnuma, Dang, & Abbreviations: AT, Adipose tissue; BP, Bullous pemphigoid; Practice Research Datalink; CD26, Cluster of differentiation Dipeptidyl peptidase 4; DPP4is, DPP4 inhibitors; EPC, Endothelial macrophage-CSF; GLP-1, Glucagon like peptide-1; GIP, Glucose IFN-γ, Interferon gamma; IL, Interleukin; LADA, Latent autoimmune drugs; PCa, Prostate cancer; Treg, Regulatory T; RA, Rheumatoid DPP4; STZ, Streptozotocin; SDF-1, Stromal cell-derived factor-1; Type 2 diabetes mellitus; UC, Ulcerative colitis. ⁎ Corresponding author at: Division of Endocrinology, Tongji E-mail address: [email protected] (Y. Chen). et al. / Pharmacology & Therapeutics 209 (2020) 107503 2.1. CD4(+) and CD8(+) T cells as on the sur- It has been previously demonstrated that higher expression of CD26 on cell surface of CD4(+) T cells is correlated with their T helper type 1 (Th1)-like phenotype, whereas the lower expression of CD26 is associ- ated with their Th2-like phenotype (Willheim et al., 1997). Further- more, high CD26 surface expression is also correlated with the production of Th1-type cytokines (Reinhold et al., 1997; Willheim et al., 1997). DCs are the most potent antigen-presenting cells (APC) specialized in the initiation of immune responses by directing the activation and differentiation of naïve T lymphocytes. Pacheco et al. reported that, in a deaminase activity-independent way, ADA interacts with CD26 on the T cell surface. The complex subsequently anchors to DC surface by an ADA-anchoring protein and then triggers costimulation, leading to an augmented T-cell activation with a Th1 pattern and a marked in- crease in the production of Th1 proimmﬂamatory cytokines including interferon gamma (IFN-γ), tumor necrosis factor (TNF)-α, and interleu- kin (IL)-6 (Pacheco et al., 2005). On the contrast, CD26 knockout in mice leads to a reduction in Th1 immune responses (Preller et al., 2007) but an up-regulation of Th2-type cytokines, such as IL-4, IL-5, and IL-13 (Yan, Gessner, Dietel, Schmiedek, & Fan, 2012). These ﬁndings further conﬁrm the importance of CD26 in the proliferation and function of Th1 and Th2 cells. IL-17-producing CD4(+) T cells (Th17 cells), the proliferation of which is regulated by IL-6, IL-23, and transforming growth factor (TGF)-β, play an important role in the pathogenesis of autoimmune in- ﬂammation; while regulatory T (Treg) lymphocytes exert their immu- nosuppressive effect by means of direct cell-to-cell interaction or through secretion of cytokines such as TGF-β and IL-10 (Shao, Yu, & Shen, 2018). It has been found that expression of enzymatically active CD26/DPP4 is higher in human Th17 cells than in Th1, Th2, or Tregs cells (Bengsch et al., 2012). Phenotypic analysis has revealed that CD26(++)CD4(+) T cells contain more than 90% of Th17 cells (Bengsch et al., 2012). CD26 knockout results in a signiﬁcant reduction of the Th17 cytokines such as IL-17 and IL-21 in mice with lung transplantation (Yamada et al., 2016). The author assumed that the modulation of Th17 cells by CD26 is via the costimulatory effects on signaling lymphocytic activa- tion (Yamada et al., 2016). However, further investigation on down- stream signaling was not performed. IL-6 is important for T cell proliferation and Th17 cells show an IL6-dependent increase (Wang et al., 2018; Winer et al., 2009). We have described that CD26 is corre- lated with augmented Th1 activation along with a marked increase of Th1 cytokines including IL-6. Pinheiro et al. found that sitagliptin treat- ment could completely abolish IL-6 expression by peripheral blood mononuclear cells (PBMCs) with the stimulation of phytohemaggluti- nin (PHA) from healthy volunteers and inhibit Th1/Th17 differentiation in vitro (Pinheiro et al., 2017). Thus, we assume that IL-6 may also be in- volved in CD26-mediated Th17 proliferation. On the contrary, CD26 expression is lower on the membranes of Treg cells (Mandapathil et al., 2010), which has been characterized as a neg- ative selection marker for human Tregs (Garcia Santana, Tung, & Gulnik, 2014). Based on CD39/CD26 marker, analysis of human natural regula- tory T cells (nTregs) has identiﬁed ﬁve different cell subsets, representing a distinct stage of maturation respectively (Schiavon et al., 2019). In addition, DPP4i signiﬁcantly increases the Treg expan- sion in non-obese diabetic (NOD) mice (Tian et al., 2010), indicating that DPP4/CD26 inhibition may be responsible for the proliferation of Treg lymphocytes. Martinez-Navio identiﬁed that ADA promotes an augmented generation of CD4(+)CD25(high)Foxp3(+) Tregs by a mechanism that seems to be mainly dependent on its enzymatic activity (Martinez-Navio et al., 2011). Accordingly, CD26/ADA/adenosine is con- sidered to exert an important regulatory role in the generation of Tregs. It has been previously demonstrated that both CD8(+)CD26(high) and CD8(+)CD26(−) cells represent activated cell phenotypes and S. Shao et al. / Pharmacology & Therapeutics 209 (2020) 107503 3 Reference with the production of Th1 (Preller et al., 2007; Reinhold et al., 1997; Willheim et al., 1997) leads to up-regulation of Th2 (Willheim et al., 1997; Yan et al., 2012) with the production of Th17 (Bengsch et al., 2012; Yamada et al., 2016) leads to up-regulation of Tregs (Garcia Santana et al., 2014; Mandapathil et al., 2010; Schiavon et al., 2019; Tian et al., 2010) co-stimulation of CD8(+) T cells (Hatano et al., 2013; Ibegbu et al., 2009) correlated with B cell activation (Buhling et al., 1995; Klemann et al., 2009; Morimoto et al., 1989; Yan et al., 2003) correlated with the proliferation and (Buhling et al., 1994; Shingu et al., 2003; Yan et al., 2003) of NK cells with ADA stimulates T-cell (Gliddon & Howard, 2002; Zhong et al., 2013) M1/M2 macrophage polarization (Shah et al., 2011; Zhuge et al., 2016) peptidase 4; NK cell, natural killer cell; Th1 cell, T helper type 1 cell; Th2 cell, T helper type 2 cell; Th17 cell, IL-17- and cell cycle progression, thus concluding that CD26 is involved in the modulation of NK cell proliferation. DPP4/CD26 may also be in- volved in the natural cytotoxicity of NK cells, which is veriﬁed by the ob- servation that NK cell cytotoxicity against tumour (MADB106) cells is diminished in a DPP4/CD26-deﬁcient F344 rat sub-strain, a model of lung metastasis (Shingu et al., 2003). One of the underlying mechanisms is that tumor target cells can directly adhere to NK cells via CD26. In ad- dition, NK cells can exert their cytotoxicity via secretory lysosomes. In- terestingly, DPP4/CD26 has been found on the membrane of secretory lysosomes in NK cells by mean of proteomic analysis (Casey, Meade, & Hewitt, 2007). Whether CD26 on secretory lysosomes could also medi- ate NK cell cytotoxicity is remained to be identiﬁed. 2.3. Dcs and macrophages The ﬁrst description of DPP4/CD26 expression on DCs was reported by Gliddon and colleagues from bovine afferent lymph and lymph nodes (Gliddon & Howard, 2002). Both obese humans and rodents demon- strated increased DPP4/CD26 expression on DCs from visceral adipose tissue (AT) (Zhong et al., 2013). It is considered that CD26 expression by DC confers the ability to modify macrophage-derived chemokine (MDC) so that it may not stimulate Th2 polarized cells but attract and induce responses in Th1 polarized cells (Gliddon & Howard, 2002). Fur- thermore, the CD26-ADA complex on DCs is capable of stimulating T cell proliferation via adenosine degradation in mixed lymphocyte reaction (MLR) assays using T-cell/DC cocultures (Zhong et al., 2013). These ﬁnd- ings disclose a novel mechanism for the paracrine regulation of inﬂam- mation in AT by DPP4. DPP4/CD26 expression on macrophages from visceral AT was also identiﬁed in both high fat diet (HFD)-induced (C57BL/6) and genetically obese (ob/ob) mice (Zhong et al., 2013). Long-term DPP4 inhibition by alogliptin decreases visceral AT macrophage content (CD11b(+), CD11c(+), Ly6C(hi)) in a ApoE (−/−) mouse model (Shah et al., 2011). Similarly, Ikedo et al. identiﬁed that alogliptin inhibits the accu- mulation of macrophages in intracranial aneurysms in SD rats and they veriﬁed that such effect is independent of GLP-1 (Ikedo et al., 2017). Silencing expression of DPP4 by shRNA targeting hepatocytes in HFD induced obese mice also suppresses macrophage inﬂammation of visceral AT (Ghorpade et al., 2018). Furthermore, Zhong and col- league reported that macrophage-expressing DPP4 binds ADA, resulting in T-cell proliferation via modulation of adenosine concentrations and then the development of adipose inﬂammation (Zhong et al., 2013). All these ﬁndings disclose the signiﬁcant role of DPP4/CD26 on macro- phage proliferation and function. et al. / Pharmacology & Therapeutics 209 (2020) 107503 Table 2 Known/potential factors truncated/regulated by DPP4/CD26. Substrate Reference Chemokines CCL2 (MCP-1) (Qin et al., 2018) CCL3 (MIP-1α) (Zhuge et al., 2016) CCL5 (RANTES) (Oravecz et al., 1997) CCL11 (Eotaxin) (Hollande et al., 2019) CCL22 (MDC) (Gliddon & Howard, 2002; Proost et al., 1999) CXCL10 (IP-10) (Barreira da Silva et al., 2015; Proost et al., 2001) CXCL11 (I-TAC) (Proost et al., 2001) CXCL12 (SDF-1) (De La Luz Sierra et al., 2004; Janssens et al., 2017) Mig (Proost et al., 2001) Cytokines IL-3 (Broxmeyer et al., 2012; O'Leary et al., 2017) GM-CSF (Broxmeyer et al., 2012) G-CSF (Broxmeyer et al., 2012) Erythropoietin (Broxmeyer et al., 2012) FGF2 (Wesley et al., 2005) IL-1⁎ (Ou et al., 2013) IL-2⁎ (Ou et al., 2013) et al., 2017; IL-5⁎ (Ou et al., 2013) IL-6⁎ (Ou et al., 2013) IL-8⁎ (Ou et al., 2013) IL-10⁎ (Ou et al., 2013) TGF-β# (Steinbrecher et al., 2001) IFNγ# (De Meester et al., 1994; Kameoka et al., 1993) 2), thereby, TNF-α# (De Meester et al., 1994; Kameoka et al., 1993) Incretin hormones Gastric inhibitory peptide (Ahren & Hughes, 2005) (GIP) Gastrin-releasing peptide (Ahren & Hughes, 2005) (GRP) GLP-1 (Baggio & Drucker, 2007) GLP-2 (Baggio & Drucker, 2007) he- Peptide YY(1–36) (Unniappan et al., 2006) Neuropeptides NPY (Frerker et al., 2007) through Substance P (Guieu et al., 2006) CCL, C-C motif chemokine ligand; CXCL, Chemokine (C-X-C motif) ligand; FGF2, ﬁbroblast growth factor 2; G-CSF, Granulocyte-CSF; GIP, Gastric inhibitory peptide; GLP, hormones glucagon like peptide; GM-CSF, Granulocyte-macrophage-colony-stimulating factor; GRP, Gastrin-releasing peptid; IL, interleukin; IFNγ, interferon gamma; IP-10, IFN- gamma-inducible protein-10; I-TAC, IFN-inducible T-cell alpha-chemoattractant; MCP-1, monocyte chemotactic protein 1; MDC, macrophage-derived chemokine; Mig, monokine induced by IFN-gamma; MIP-1α, Macrophage inﬂammatory protein-1α; NPY, neuropeptideY; SDF-1, stromal cell-derived factor-1; RANTES, regulated on activation in normal T-cell expressed and secreted; TGF-β, transforming growth factor-β; TNF-α, tumor necrosis factor-α. ⁎ Potential truncation by DPP4/CD26. # Regulation rather than truncation by DPP4/CD26. 3. Effects and underlying mechanisms of DPP4/CD26 inhibition on immunotherapy DPP4is have been linked to the diseases as summarized in Table 3, including but not limited to autoimmune diabetes, inﬂammatory bowel disease (IBD), rheumatoid arthritis (RA), allograft rejection, tumor, cardiovascular disease (CVD), asthma, infectious diseases and bullous pemphigoid (BP). However, the effect of DPP4is on these dis- eases is controversial. secretion 3.1. DPP4/CD26 inhibition on autoimmune diseases stimulate 3.1.1. DPP4/CD26 inhibition on autoimmune diabetes Type 1 diabetes mellitus (T1DM) is an autoimmune disorder charac- terized by the destruction of pancreatic β cells and inadequate insulin secretion (Roep & Tree, 2014). Under this circumstance, even slight preservation of residual β cell mass may result in signiﬁcant beneﬁts in clinic (Palmer et al., 2004). Unfortunately, there are no immunomod- ulatory drugs that have been reported to induce/assist the disease S. Shao et al. / Pharmacology & Therapeutics 209 (2020) 107503 5 remission. Currently, DPP4is are widely applied as valuable mono- or combination therapeutic OADs for T2DM. However, only a portion of clinical studies have indicated potential efﬁcacy regarding glycemic al., 2011; Farngren et al., control and β cell preservation in T1DM. Autoimmune diabetes is characterized by an increased Th1 immune et al., 2013; Hari Kumar response and a decreased Th2 response. In addition, the imbalance of 2013; Zhao et al., 2014) Th17/Treg is also involved in the pathogenic process (Shao et al., et al., 2014; Zhao 2012). It has been described in Table 1 that DPP4 inhibition down- et al., 2014; Hari Kumar regulates Th1-like phenotype, up-regulates Th2-type cytokines, stimu- lates the proliferation of Tregs, and decreases IL-17 production. Thus, et al., 2003; Jelsing DPP4is are supposed to have the potential to treat autoimmune diabetes. 2012; Kim et al., 2012; In preclinical trials, inhibition of DPP4 activity has been shown to en- 2008; Pospisilik et al., et al., hance islet neogenesis and β cell survival, and reverse/delay the onset et al., 2012; Tian of diabetes in either streptozotocin (STZ)-induced animal model of T1DM (Conarello et al., 2003; Pospisilik et al., 2003; Takeda et al., et al., 2018; Kridin 2012) or NOD mouse model of autoimmune diabetes (Jelsing, Vrang, 2018; Wang et al., 2019) van Witteloostuijn, Mark, & Klein, 2012; Tian et al., 2010). A combination 2011; Salaga et al., therapy of DPP4i and proton pump inhibitor (PPI) increases circulating 2015; Seong et al., levels of GLP-1 and gastrin in acutely diabetic NOD mice, resulting in the restoration of pancreatic insulin content, insulin secretion and normoglycaemia (Suarez-Pinzon, Cembrowski, & Rabinovitch, 2009). al., 2005; Ospelt et al., Treatment of STZ-induced T1DM mice with DPP4i MK0431 before and after islet transplantation prolongs the survival of islet grafts (Kim et al., 2008). Differently, Kim et al. reported that β cell mass is enhanced in NOD mice by the combination of Toll-like receptor 2 (TLR2) agonist al., 2012; Green and DPP4i, but not by DPP4i or TLR2 agonist alone (Kim et al., 2012). 2015; Leiter, et al., 2015; al., 2016) Most of the previous animal studies considered that β cell preserva- da Silva et al., 2015; tion by DPP4is is attributed to an increase in GLP-1 (Conarello et al., et al., 2014; Hollande 2003; Kim et al., 2008; Pospisilik et al., 2003; Suarez-Pinzon et al., 2019; Nishida et al., 2018; 2009; Takeda et al., 2012). Dysfunctional Tregs are thought to be a hall- mark of T1DM (Geach, 2016). Preclinical data from Tian and colleagues al., 2018; Shingu et al., et al., 2005; Xie demonstrated that up-regulation of Tregs by DPP4 inhibition is associ- ated with the remission of NOD mice (Tian et al., 2010). It is possible al., 2018; Green et al., that DPP4 suppression results in the changes of chemokines in diabetic et al., 2013; White NOD mice and thus promotes the migration of Tregs to pancreas et al., 2013; White et al., (Fig. 1A). Due to these signiﬁcant results from animal experiments, numerous clinical studies are conducted to investigate the therapeutic effect of 2013; Kubota et al., 2016; DPP4is in patients with T1DM. Four placebo-controlled studies investi- et al., 2016; Shah et al., gated the efﬁcacy of sitagliptin/vildagliptin treatment in T1DM (Ellis et al., 2013; et al., 2011; Farngren, Persson, Schweizer, Foley, & Ahren, 2012; Garg et al., 2016; Yin et al., et al., 2013; Hari Kumar, Shaikh, & Prusty, 2013). Two studies showed signiﬁcant HbA1c reduction of −0.27 and − 0.34% after DPP4is treat- al., 2012) ment for 8 or 4 weeks, respectively (Ellis et al., 2011; Farngren et al., al., 2010) 2012), while the other two studies didn't show any treatment-related differences (Garg et al., 2013; Hari Kumar et al., 2013). A meta- analysis from Wang et al. revealed that the additional use of DPP4is re- sults in a greater decrease in HbA1c levels compared to insulin mono- therapy, although it is not signiﬁcant (Wang, Long, et al., 2018). Additionally, some trials investigated the effect of gliptins on β cell 2018; Raj et al., 2013) preservation. In individuals with newly diagnosed T1DM, sitagliptin treatment for one year failed to result in any signiﬁcant difference of et al., 2016; Riva et al., c-peptide secretion between groups (Hari Kumar et al., 2013). Likewise, al., 2019; Goodwin Grifﬁn and colleagues randomly assigned T1DM participants to receive a combined therapy of oral sitagliptin and a PPI lansoprazole or matched et al., 2013; Arai et al., placebo for 12 months; however, the difference of c-peptide between groups is not signiﬁcant (Grifﬁn, Thompson, Gottschalk, Kyllo, & et al., 2018; Douros Rabinovitch, 2014). These two trials estimated that gliptins are incapa- 2019; Garcia et al., 2016; Bergman, 2018; Lee ble of preserving β cell mass in autoimmune diabetes. Latent autoim- 2019; Plaquevent, et al., mune diabetes in adults (LADA) is a special subtype of T1DM. et al., 2018) Interestingly, a one-year prospective study conducted in LADA patients CRC, colorectal cancer; demonstrated that a combined treatment of sitagliptin to these patients HCV, hepatitis C virus; HIV, who receive insulin provides signiﬁcant improvements in the parame- LADA, Latent autoim- ters of islet function (Zhao et al., 2014). Similarly, another DPP4i, Pca, prostate cancer; linagliptin, contributes to a progressive increase in c-peptide levels in type 2 diabetes mellitus. patients with LADA during a 2-year study (Johansen et al., 2014). et al. / Pharmacology & Therapeutics 209 (2020) 107503 in autoimmune diabetes (A), inﬂammatory bowel disease (B), rheumatoid arthritis (C). Administration's Adverse Event Reporting System (FAERS) database (Wang et al., 2019). Li et al. performed a meta-analysis of randomized controlled trials (RCTs) and no association between DPP4i and IBD was found. Howbeit, sub-analysis identiﬁed that DPP4i OADs may reduce CD risk but in- crease UC risk (Li et al., 2019). Of note, this analysis may have been un- derpowered to detect such an association due to the limited number of included trials/events and the statistical imprecision. Thus, we suggest that the association between DPP4is and IBD should be noted by physi- cians. It should be cautious when treating diabetic patients with IBD. 3.1.3. DPP4/CD26 inhibition on RA RA is a chronic, systemic inﬂammatory disease with unknown etiol- ogy and is characterized by progressive destruction of articular cartilage and erosion of the underlying bone (Speiser, Ho, & Verdeil, 2016). Altered DPP4 activity was ﬁrst noted in mice with RA in 1989 (Gotoh, Hagihara, Nagatsu, Iwata, & Miura, 1989). To gain insights into the pathophysiological role of CD26 in arthritis, Busso et al. explored DPP4 expression in experimental mice model of arthritis, murine antigen-induced arthritis (AIA), and found a reduced plasma DPP4 ac- tivity in those mice models (Busso et al., 2005). Secretion of CXCL12/ SDF-1, the substrate of DPP4, by RA synovial ﬁbroblasts (RASFs) is cru- cially involved in the inﬂammatory process by recruitment of CXCR4- expressing T cells and monocytes from the periphery into the rheuma- toid synovium (Seki, Selby, Haupl, & Winchester, 1998). In CD26- deﬁcient mice with AIA, the disease severity is increased due to a lower DPP4 activity in synovial ﬂuids, which results in an increase in SDF-1 levels in those mice (Fig. 1C) (Busso et al., 2005). The major extra- cellular proteolytic enzymes involved in cartilage resorption are matrix metalloproteinases (MMPs) and serine proteases (Proost et al., 2001). Ospelt et al. found that inhibition of serine protease activity of DPP4 pro- motes invasion of RASFs into cartilage in a mouse model of RA and leads to an increase in SDF-1 levels in concert with its downstream effectors MMP-1 and MMP-3 in vitro (Ospelt et al., 2010). These results indicate a central role of DPP4/SDF-1 signaling in protecting articular cartilage against RASFs invasion. Busso et al. explored DPP4 expression in RA patients and also found a reduced plasma DPP4 activity (Busso et al., 2005). The concentration of SDF-1 is greatly elevated in the synovial ﬂuid from patients with RA in contrast to its concentration in healthy individuals (Kanbe, Takagishi, & Chen, 2002). However, the functional role of DPP4/CD26 in human observed in the present cohort ﬁndings contradicts that in animal stud- ies. In a large cohort of diabetic patients, those initiating DPP4i combina- tion therapy appeared to have a decreased risk of autoimmune diseases including RA (hazard ratio 0.66) compared with those initiating non- DPP4i combination therapy (Kim et al., 2015). Similar result was found in a large population-based cohort study conducted by Seong (Seong, Yee, & Gwak, 2019). However, using the United Kingdom CPRD, Douros conducted a cohort study among 144,603 patients with T2DM initiating OADs between 2007 and 2016, and found that use of Shao et al. / Pharmacology & Therapeutics 209 (2020) 107503 7 inhibition in allograft rejection (A), cancer (B), cardiovascular disease (C), and asthma (D). pulmonary transplantation in animal models (Jung et al., 2006; Zhai et al., 2007). A recent study from Yamada group concluded that CD26 blockade promotes lung allograft acceptance due to reduced T cell inﬁl- tration, lower expression of IL-17 and IL-21, and increased expression of IL-10, which is likely to be derived from alternatively activated macro- phages (Yamada et al., 2016). These results expand the role of DPP4/ CD26 in alloantigen-mediated immune responses. Moreover, CD26 knockout mice have been used to investigate the potential role of DPP4 in allogeneic skin graft rejection. It is shown that CD26 knockout mice display a reduced necrosis of grafts and a de- layed graft rejection with signiﬁcantly reduced secretion levels of the cytokines such as IFN-γ, IL-2, IL-6, IL-4, IL-17, and IL-13 but increased level of IL-10 after skin transplantation (Zhao et al., 2019). Additionally, a lower percentage of Th17 and CD8(+) T cells but a higher percentage of Treg cells are detected in peripheral blood lymphocytes of CD26 knockout mice in the same study (Zhao et al., 2019), indicating that CD26 deﬁciency leads to feebler rejection due to lower activation and less proliferation of host immune cells. So far, there is still few clinical studies focusing on the potential ef- fect of DPP4i on allograft rejection. Future investigations in this ﬁeld are necessary and may expand the clinic application of DPP4is. 3.2.2. DPP4/CD26 inhibition on cancer Increasing evidences have demonstrated that the application of im- munotherapy can improve the clinic outcome of cancer. Encouraging ﬁndings from experimental works regarding DPP4/CD26 suppression in melanoma, liver and breast tumors (Barreira da Silva et al., 2015; Herrmann et al., 2014; Hollande et al., 2019; Nishida, Hayashi, Morimoto, Sakamoto, & Yamada, 2018; Qin et al., 2018) pave the way et al. / Pharmacology & Therapeutics 209 (2020) 107503 5–7 days after MI (Hocher, Sharkovska, Mark, Klein, & Pfab, 2013; Kubota et al., 2016). Endothelial progenitor cells (EPCs) derived from the bone marrow are known to promote vascular repair and neoangiogenesis. Importantly, it has been revealed that inhibition of DPP4 potentially enhances the delivery of EPCs towards injured vascu- lar sites after MI in rats (Hocher et al., 2013), probably due to an in- creased concentration of SDF-1 (Fig. 2C). A 4-week clinic trial in T2DM patients treated with linagliptin identiﬁed a signiﬁcant increase in EPCs and SDF-1 (Fadini et al., 2010). In addition to EPCs, we have de- scribed that SDF-1 could also attract other stem cells through the CXCR4. Zhang et al. reported that the combination of overexpression of CXCR4 in mesenchymal stem cells (MSC) with diprotin A, a DPP4 inhibiter, in rat MI model enhances MSC recruitment and penetration into ischemic myocardium via SDF-1 pathway, leading to the inhibition of myocardial ischemia-induced apoptosis, tissue angiogenesis, and an improvement in heart function after MI (Zhang et al., 2010). Further- more, the cardioprotective effect is abolished by the pretreatment with a CXCR4 antagonist or a signal transducer and activator of tran- scription 3 (STAT3) inhibitor in mice with MI, indicating that DPP4 inhi- bition may have direct protective effects on the post-MI heart through SDF-1/CXCR4-mediated STAT3 signaling pathway (Kubota et al., 2016). Fadini also reported a proﬁle of increased CD34(+)CD133(+) progenitor cells, CD34(+)KDR(+) EPCs, and CX3CR1(bright) mono- cytes along with signiﬁcantly elevated SDF-1 in T2DM patients with 4- day treatment of linagliptin (Fadini et al., 2016), which further demon- strates the potential favorable cardiovascular implications of gliptins. In contrast, chronic administration of vildagliptin to normoglycemic rats either prior to or after 12 weeks' induction of MI fails to avert the reduction of ejection fraction or modify cardiac remodeling (Yin, Sillje, Meissner, van Gilst, & de Boer, 2011). The inconsistent ﬁndings may be attributed to the long duration of disease, and it is accordingly as- sumed that DPP4 inhibition has no substantial protective effects on car- diac function in this well established long-term post-MI cardiac remodeling model. Reduced interstitial ﬁbrosis in hearts is observed in MK-0626 (a se- lective DPP4i)-treated C57BL/6 J mice fed a high fat/high fructose diet for 16 weeks (Bostick et al., 2014). In consistence with these ﬁndings, Mulvihill et al. identiﬁed that young normoglycemic DPP4(−/−) mice also exhibit a signiﬁcant reduction in cardiac ﬁbrosis and a cardioprotective response after transverse aortic constriction (TAC) sur- gery (Mulvihill et al., 2016). Surprisingly, diabetic mice treated with MK-0626 exhibit modest cardiac hypertrophy, impairment of cardiac function, and dysregulated expression of genes and proteins involved in inﬂammation and cardiac ﬁbrosis (Mulvihill et al., 2016). We as- sumed that metabolic status may affect the cardiovascular beneﬁts from DPP4 inhibition, which is remained to be investigated. Although clinical studies have emphasized cardiovascular safety, no evidences of reduced major adverse cardiovascular events with differ- ent DPP4is were observed (Aroor et al., 2018; Green et al., 2015; Scirica et al., 2013; White et al., 2013). More than that, some cardiovas- cular outcome trials revealed an increase in hospitalization rates for heart failure (HF) among subjects treated with saxagliptin or alogliptin (Scirica et al., 2013; White et al., 2013). According to these results, it is speculated that the cardiovascular beneﬁts from DPP4 inhibition may be dependent on the disease dura- tion (transient or long-term) and metabolic phenotype (diabetic or non-diabetic), which may explain, at least in part, the insigniﬁcant cardioprotective effect of DPP4is in T2DM patients. Further clinical stud- ies to investigate these factors may be of importance. 3.2.4. DPP4/CD26 inhibition on asthma Allergic asthma is a disease that causes the swelling and narrowing of airways, resulting in wheezing, shortness of breath and coughing (Umetsu, McIntire, Akbari, Macaubas, & DeKruyff, 2002). Whether CD26/DPP4 plays a role in the pathogenesis of asthma or allergic-like airway inﬂammation is still controversial. et al. / Pharmacology & Therapeutics 209 (2020) 107503 9 immune-suppressive cytokine IL-10 and protective growth factor epi- dermal growth factor (EGF) are signiﬁcantly negatively and positively correlated with plasma sDPP4 concentration, respectively (Inn et al., 2018). Thus, it is assumed that exogenous sDPP4 may have therapeutic potential in MERS patients and that application of gliptins in MERS pa- tients may adversely affect the pathological and immune processes of this disease. Conversely, increased sDPP4 activity was found in chronic infections by hepatitis C virus (HCV), hepatitis A virus (HAV), and Epstein-Barr virus (Andrieu et al., 2003). The pathogenesis of HCV infection is strongly inﬂuenced by the nature of the host's antiviral immunity. It has been described that CXCL10 can be truncated by DPP4 (Table 2). Riva et al. reported that subjects developing chronic hepatitis C have higher concentrations of truncated CXCL10 and DPP4 activity; whereas DPP4 activity progressively decreases over time in patients who sponta- neously clears the infection (Riva et al., 2014). A follow-up study was conducted to test the effects of DPP4 inhibition on CXCL10 processing in chronic HCV patients. Participants were treated daily with 100 mg sitagliptin, which results in a signiﬁcant decrease in truncated CXCL10 but a reciprocal increase in full length form (Decalf et al., 2016). These data provide the direct evidence that therapeutic abrogation of DPP4 ac- tivity by gliptins in humans can preserve the bioactive form of CXCL10, suggesting that DPP4i may be a novel strategy to target both the virus and the host (Fig. 3). In addition, DPP4is can block RANTES cleavage, thereby potentially facilitating human immunodeﬁciency virus (HIV) entry into T lympho- cytes (Lusso et al., 2011), and inhibit cleavage of SDF-1, potentially blocking HIV entry into T lymphocytes (Bleul et al., 1996). Accordingly, it is signiﬁcant to evaluate the immune and virological safety of DPP4 in- hibition in HIV. Dube et al. evaluated inﬂammation and immune markers during treatment with the sitagliptin among virologically sup- pressed HIV patients without diabetes. It is found that sitagliptin has no effect on sCD14 levels, a biomarker of monocyte activation (Dube et al., 2019). In addition, there are no differences in any of the immune markers except a signiﬁcant fall in CXCL10 (Dube et al., 2019). Similar investigation was performed by Goodwin which indicated that, despite there on HF my- with than ob- effect of However, a They ana- increases to ﬁgure respira- Interest- through is known that Inn and col- Fig. 3. The underlying mechanisms of DPP4 inhibition in infectious diseases. al. / Pharmacology & Therapeutics 209 (2020) 107503 3.3. DPP4/CD26 inhibition and BP BP is a potentially severe autoimmune skin disease, the typical clin- ical features of which include the widespread blisters, often preceded by or associated with urticarial or eczema-like lesions (Tasanen, Varpuluoma, & Nishie, 2019). Currently, DPP4i-associated BP is attracting increasingly attentions. Howbeit, the pathogenesis and underlying mechanisms remain unclear. It has been shown that inhibition of DPP4 in F344 rats induces the inﬁl- tration of eosinophils into the skin (Fig. 4) (Forssmann et al., 2008), which is a typical histopathologic feature of BP. The major BP autoantigen BP180, known as a transmembrane collagen XVII, is re- sponsible of anchoring epidermis into the underlying dermis. Under the condition of BP, anti-BP180 autoantibodies could impair BP180 function, leading to dermal-epidermal separation (Algaissi et al., 2019). It should be noted that DPP4 converts plasminogen to plasmin, which is known to cleave BP180 into 120 and 97 kDa fragments (Hofmann et al., 2009; Nishimura et al., 2016). Accordingly, it is specu- lated that the suppression of DPP4 may be involved in the disruption of BP180 immunotolerance and the subsequent development of epitopes for BP autoantibodies. Further studies are needed to elucidate the de- tailed mechanisms. Over the last few years, case reports and pharmacovigilance analyses have suggested a risk of BP after the application of DPP4is, and the highest risk are observed with linagliptin and vildagliptin (Aouidad et al., 2013; Bene, et al., 2016). Studies from European and French pharmacovigilance databases were the ﬁrst epidemiological investiga- tions which identify a high BP incidence in gliptins treated T2DM pa- tients (Bene, et al., 2016; Garcia, Aranburu, Palacios-Zabalza, Lertxundi, & Aguirre, 2016). More recently, Douros et al. conducted a cohort study using the U.K. CPRD among 168,774 patients taking OADs and found that current use of DPP4is doubles the risk of BP, albeit the absolute incidence is low. Moreover, hazard risks gradually in- creased along with the extension of use, reaching a peak after 20 months' application of gliptins (Douros et al., 2019). Likewise, a sim- ilar increase was also observed in a Japanese pharmacovigilance database, particularly among patients treated with vildagliptin, linagliptin, or teneligliptin (Arai, Shirakawa, Konishi, Sagawa, & Terauchi, 2018). mechanisms of DPP4 inhibition in bullous pemphigoid. et al. / Pharmacology & Therapeutics 209 (2020) 107503 11 Declaration of Competing Interest or a The authors declare that there are no conﬂicts of interest. Acknowledgments Benzaquen This work was supported by a grant from Tongji Hospital in HuaZhong University of Science and Technology [grant number 2201103295 to Y Chen]; National Natural Science Foundation of China [grant number 81100581]; a grant from the Bethune·Merck Diabetes Research Fund [grant number 2018 to S Shao]; and a grant from Cardiac rehabilitation and metabolic therapy research fund [grant number 2018 to S Shao]. a relatively References such as Abbott, C. A., Yazbeck, R., Geier, M. S., Demuth, H. U., & Howarth, G. S. (2006). 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