Quantitative Phosphoproteomics Identified a New Syk-Lyn-Axl Signalling Pathway Involved In Resistance to Nilotinib In Chronic Myeloid Leukemia Cells.

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 3376-3376
Author(s):  
Romain Gioia ◽  
Cedric Leroy ◽  
Claire Drullion ◽  
Valérie Lagarde ◽  
Serge Roche ◽  
...  
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Tyrosine Kinase ◽  
Myeloid Leukemia ◽  
Conflicts Of Interest ◽  
Critical Role ◽  
Dependent Manner ◽  
Stable Isotope Labelling ◽  
Resistant Cells

Abstract Abstract 3376 Nilotinib has been developed to overcome resistance to imatinib, the first line treatment of chronic myeloid leukemia (CML). To anticipate resistance to nilotinib, we generate nilotinib resistant CML cell lines in vitro to characterize mechanisms and signaling pathways that may contribute to resistance. Among the different mechanisms of resistance identified, the overexpression of the Src-kinase Lyn was involved in resistance both in vitro, in a K562 cell line (K562-rn), and in vivo, in nilotinib-resistant CML patients. To characterize how Lyn mediates resistance, we performed a phosphoproteomic study using SILAC (Stable Isotope Labelling with Amino acid in Cell culture). Quantification and identification of phosphotyrosine proteins in the nilotinib resistant cells point out two tyrosine kinases, the spleen tyrosine kinase Syk and the UFO receptor Axl. The two tyrosine kinase Syk and Axl interact with Lyn as seen by coimmunopreciptation. Syk is phosphorylated on tyrosine 323 and 525/526 in Lyn dependent manner in nilotinib resistant cells. The inhibition of Syk tyrosine kinase by R406 or BAY31-6606 restores sensitivity to nilotinib in K562-rn cells. In parallel, the inhibition of Syk expression by ShRNA in K562-rn cells abolishes Lyn and Axl phosphorylation and then interaction between Lyn and Axl leading to a full restoration of nilotinib efficacy. In the opposite, the coexpression of Lyn and Syk in nilotinib sensitive K562 cells induced resistance to nilotinib whereas a Syk kinase dead mutant did not. These results highlight for the first time the critical role of Syk in resistance to tyrosine kinase inhibitors in CML disease emphasizing the therapeutic targeting of this tyrosine kinase. Moreover, Axl, which is already a target in solid tumor, will be also an interesting pathway to target in CML. Disclosures: No relevant conflicts of interest to declare.

ABCG2 C.421C>A Is Associated with Higher Trough Imatinib Plasma Levels in Patients with Chronic Myeloid Leukemia.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 110-110
Author(s):  
Naoto Takahashi ◽  
Masatomo Miura ◽  
Stuart A Scott ◽  
Kenichi Sawada
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Plasma Levels ◽  
Myeloid Leukemia ◽  
Drug Transport ◽  
Conflicts Of Interest ◽  
Nucleotide Polymorphisms ◽  
Wild Type ◽  
Large Patient

Abstract Abstract 110 [Background] Despite the excellent efficacy of imatinib for the treatment of chronic myeloid leukemia (CML), trough imatinib plasma levels can vary widely among patients. This may be due, in part, to inter-individual variation in imatinib metabolism and drug transport efficacy. To investigate the role of genetic variation in the pharmacokinetics of imatinib, we analyzed common single nucleotide polymorphisms within important imatinib pathway genes including ABCG2 (BCRP), ABCB1 (MDR1), ABCC2 (MRP2), CYP3A5, and SLC22A1 (OCT1) in 67 CML patients treated with imatinib. In addition, trough imatinib plasma levels were determined using high-performance liquid chromatography-tandem mass spectrometry. [Results] Distinct imatinib pharmacokinetics were identified in association with ABCG2 c.421C>A (p.Q141K; rs2231142) genotype. Specifically, the presence of the variant c.421A allele was significantly (p=0.024) associated with higher imatinib concentrations [median Cmin/Dose 2.70 (range: 1.50-8.30) ng/ml/mg; n=25] compared to patients with the wild-type ABCG2 (c.421C/C) genotype [median Cmin/Dose 2.27 (range: 0.37-5.30) ng/ml/mg; n=42]. ABCG2 is an efflux transporter for many xenobiotics, including imatinib, and is expressed at high levels in the human liver. Previous studies indicate that c.421A causes a 40% reduction in imatinib transport in vitro when compared to the wild-type genotype. Our data suggest that CML patients with ABCG2 c.421A allele may have deficient ABCG2 activity in vivo, resulting in reduced hepatic excretion of imatinib. Of note, although less common among Africans and individuals of European decent, the ABCG2 c.421C>A allele occurs at a high frequency in the Japanese (0.311) and Han Chinese (0.289) populations. [Conclusion] The association of ABCG2 c.421C>A with imatinib pharmacokinetics may explain why some Japanese CML patients administered less than 400 mg/day of imatinib have clinically sufficient trough imatinib plasma levels. Prospective studies are warranted to confirm the association between ABCG2 genotype and imatinib pharmacokinetics in large patient populations. Disclosures: No relevant conflicts of interest to declare.

Therapeutic Immune Monitoring of Chronic Myeloid Leukemia Patients Treated with Tyrosine Kinase Inhibitors: Focus on CD4+ CD25+ t Cells

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 4036-4036
Author(s):  
Ziyuan Lu ◽  
Na Xu ◽  
Xuan Zhou ◽  
Guanlun Gao ◽  
Lin Li ◽  
...  
Keyword(s):  
T Cells ◽  
Chronic Myeloid Leukemia ◽  
Tyrosine Kinase ◽  
Tyrosine Kinase Inhibitors ◽  
Myeloid Leukemia ◽  
Kinase Inhibitors ◽  
Conflicts Of Interest ◽  
Chronic Phase ◽  
Similar Proportion

Abstract Background and Objectives: In clinical, conventional Tyrosine Kinase Inhibitors (TKIs) including imatinib, dasatinib, and nilotinib are remarkably effective forms of therapy for certain types of solid cancers as well as Ph+ leukemias. In addition to the BCR-ABL target oncoprotein, they also inhibit certain off-target kinases (Eph, c-KIT, TEC, SRC). Some TKIs affect immune reconstitution as well as the proliferation, function, and activation of T cells. Certain TKIs have been known to have an especially strong effect on CD4+CD25+ T cells, also known as regulatory T Cells (Tregs). There is currently a gap in the clinical data available about on this area of study. Patients and methods: In this study, we collected 108 Peripheral Blood (PB) samples from patients in the Chronic Phase (CP) of Chronic Myeloid Leukemia (CML) at the time of diagnosis (n=31) and also the TKIs treatment. Groups consisted of individuals treated with TKIs like imatinib (n=12), dasatinib (n=11) and nilotinib (n=8), as well as healthy controls (n=15). We evaluated the quantity and function of Tregs from patients in the CML-CP at the time of diagnosis and during treatment with TKIs. Results: It was found that at diagnosis, patients with CML had a similar proportion and absolute number of lymphocytes compared to healthy donors. After TKIs treatment, proportions and absolute numbers of total T cellsACD4+ T cells and Tregs decreased at different degree. Moreover, thedecrease would be more and more significant as time goes on.Our results indicated that although these three TKIs show similar inhibitory effects in the proportion and number of Tregs in vivo, they have differential effects on the functions of Tregs in vitro. The proliferation, suppression, and expression of suppressive cytokines (IL-4,IL-10 and TGF-β) as well as suppression-associated molecules (FoxP3, GITR, and CTLA-4) of Tregs decreased in groups treated with imatinib and dasatinib. The decrease was not significant in the nilotinib-treated group. Conclusions: The results showed that imatinib and dasatinib have stronger inhibitory roles than nilotinib when it comes to regulating the number and functions of Tregs. These findings can be used to argue in favor of calls for personalized treatment and follow-up of CML patients during TKIs treatment, particularly for those patients who received combination therapy with allo-transplantation and post-transplant TKIs. Disclosures No relevant conflicts of interest to declare.

scholarly journals YBX1 is required for maintaining myeloid leukemia cell survival by regulating BCL2 stability in an m6A-dependent manner

Blood ◽  
2021 ◽  
Author(s):  
Mengdie Feng ◽  
Xueqin Xie ◽  
Guoqiang Han ◽  
Tiantian Zhang ◽  
Yashu Li ◽  
...  
Keyword(s):  
Cell Survival ◽  
Myeloid Leukemia ◽  
Rna Binding ◽  
Rna Binding Proteins ◽  
Critical Role ◽  
Leukemia Cell ◽  
Dependent Manner ◽  
Myeloid Leukemia Cell

RNA-binding proteins (RBPs) are critical regulators of transcription and translation that are often dysregulated in cancer. Although RBPs are increasingly appreciated as being important for normal hematopoiesis and for hematological malignancies as oncogenes or tumor suppressors, essential RBPs for leukemia maintenance and survival remain elusive. Here we show that YBX1 is specifically required for maintaining myeloid leukemia cell survival in an m6A-dependent manner. We found that expression of YBX1 is significantly upregulated in myeloid leukemia cells, and deletion of YBX1 dramatically induces apoptosis, promotes differentiation, coupled with reduced proliferation and impaired leukemic capacity of primary human and mouse acute myeloid leukemia (AML) cells in vitro and in vivo. Loss of YBX1 does not obviously affect normal hematopoiesis. Mechanistically, YBX1 interacts with IGF2BPs and stabilizes m6A-tagged RNA. Moreover, YBX1 deficiency dysregulates the expression of apoptosis-related genes, and promotes mRNA decay of MYC and BCL2 in an m6A-dependent manner, which contributes to the defective survival due to YBX1 deletion. Thus, our findings uncover a selective and critical role of YBX1 in maintaining myeloid leukemia survival that might provide a rationale for the therapeutic targeting of YBX1 in myeloid leukemia.

Synergic Effects of Proteasome Inhibitor PS-341 and Tyrosine Kinase Inhibitor STI571 on Chronic Myeloid Leukemia Cells and BCR-ABL Oncoprotein In Vitro and In Vivo.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 4771-4771
Author(s):  
Guangbiao Zhou ◽  
Zheng Hu ◽  
Dapeng Liu ◽  
Fuqun Wu ◽  
Jiang Zhu ◽  
...  
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Tumor Growth ◽  
Proteasome Inhibitor ◽  
Myeloid Leukemia ◽  
K562 Cells ◽  
Leukemic Cells ◽  
Great Promise ◽  
Dependent Manner

Abstract STI571/Gleevec/imatinib, a rationally-designed agent that occupies the ATP-binding site of BCR-ABL and stabilizes the protein in its closed, inactive conformation, has been a remarkable success for the treatment of chronic myeloid leukemia (CML). However, a significant proportion of patients chronically treated with STI571 develop resistance because of the acquisition of mutations in the kinase domain of BCR-ABL. Furthermore, the effects of STI571 on CML patients in accelerated phase or blastic crisis are unsatisfactory since many patients relapse after transient remission. Hence, additional drugs or STI571-based combination regimens are desired to circumvent resistance and to improve response rates. Here we reported that PS-341, a proteasome inhibitor which offers great promise to patients with multiple myeloma (MM), significantly enhanced the antileukemia activity of STI571 in vitro and in vivo. We found a synergy exists between low concentrations of PS-341 (5–10 nM) and STI571 (0.1–0.2 μM) in inhibition of cell growth and induction of apoptosis in K562 cell line and CD34+ leukemic cells isolated from CML patients. In K562 cells, combined use of PS-341 and STI571 accelerated activation of caspase-3, 9, and facilitated cleavage of poly-(ADP-ribose) polymerase (PARP) as compared to those in cells treated with PS-341 or STI571 alone. Moreover, PS-341/STI571 combination resulted in potentiated degradation of BCR-ABL and downregulation of phosphorylated BCR-ABL as compared to those in mono treatment. In nude mice inoculated subcutaneously with K562 cells, treatment with PS-341 (injected intraperitoneally, ip) alone (at doses of 0.05, 0.5, 1 mg/kg/d, twice a week for 4 weeks, respectively) decreased tumor growth in a dose-dependent manner. STI571 (ip) at 10 mg/kg/d also inhibited tumor growth. Intriguingly, combinatory administration of low dose PS-341 (0.05 mg/kg/d, twice a week for 4 weeks) and STI571 (10 mg/kg/d) yielded a much more profound inhibition of tumor growth and even clearance of leukemic cells in mice compared to either monotherapy. Taken together, these results demonstrate synergic effects of PS-341 and STI571, and provide the rationale to evaluate PS-341/STI571 combination in treating CML aiming to further improve clinical outcome of patients.

scholarly journals Different Classes of ABL1 Fusions Activate Different Downstream Signalling Nodes

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 2628-2628
Author(s):  
Lauren M Brown ◽  
Hannah Huckstep ◽  
Jarrod Sandow ◽  
Ray C Bartolo ◽  
Nadia Davidson ◽  
...  
Keyword(s):  
Tyrosine Kinase ◽  
Kinase Inhibitors ◽  
Conflicts Of Interest ◽  
Sh2 Domain ◽  
Signalling Pathways ◽  
Stable Isotope Labelling ◽  
In Vivo Models ◽  
Sh3 Domains

Abstract Background: Philadelphia-like acute lymphoblastic leukaemia (Ph-like ALL) is a high-risk subtype of ALL driven by a range of tyrosine kinase and cytokine receptor rearrangements. ABL1-class rearrangements (ABL1, ABL2, CSF1R and PDGFRB) account for 17% of Ph-like ALL cases in children, and are clinically important to identify as they can be therapeutically targeted with tyrosine kinase inhibitors (TKIs). While the p190 BCR-ABL1 fusion is well described, less is known about the function and downstream signalling by rare ABL1 fusions. We identified a rare ABL1 fusion, SFPQ-ABL1, in a paediatric B-ALL patient using RNA-sequencing. This fusion lacks the ABL1 Src-homology-3 (SH3) and part of the SH2 domain, which are retained in BCR-ABL1. Other ABL1 fusions, RCSD1-ABL1 and SNX2-ABL1, have a similar structure. In this work we have utilised phosphoproteomics and Stable Isotope Labelling by Amino Acids in Cell Culture (SILAC), as well as in vitro and in vivo models, to determine differential signalling pathways between SFPQ-ABL1 and BCR-ABL1. Methods: We cloned SFPQ-ABL1 from patient cDNA, and engineered SFPQ-ABL1 and BCR-ABL1 fusions to include or delete the SH2 and SH3 domains. We performed proliferation and viability assays to assess the ability of these fusions to transform Ba/F3 cells and test sensitivity to TKIs. We performed total phosphopeptide and phosphotyrosine enrichments and utilised mass spectrometry to identify the phosphoproteome activated by canonical SFPQ-ABL1 and BCR-ABL1. Over representation analysis was performed on phosphopeptides significantly differing between BCR-ABL and SFPQ-ABL (Log fold change cut-off > 2.5) using the Gene Ontology (GO) knowledge base under the biological process category. Furthermore, we compared the phosphoproteome of canonical SFPQ-ABL1 to SFPQ-ABL1 with the SH2 and SH3 domains reintroduced (SFPQ-ABL1+SH). We have also developed novel mouse models, using syngeneic transplantation, of SFPQ-ABL1 and SNX2-ABL1 driven leukaemia. Results: SFPQ-ABL1 expressing Ba/F3 cells are sensitive to cell death induced by TKIs that block ABL1. Interestingly, while SFPQ-ABL1 and BCR-ABL1 both effectively blocked apoptosis, SFPQ-ABL1 was less able to drive cytokine-independent proliferation. Phosphoproteomic analysis showed that BCR-ABL1 and SFPQ-ABL1 differentially activate downstream signalling pathways, including SH-binding proteins. Hierarchical clustering of phosphopeptides quantified from cells expressing canonical BCR-ABL1, SFPQ-ABL1, and SFPQ-ABL1+SH, demonstrated that BCR-ABL1 and SFPQ-ABL1+SH were more similar to each other than to SFPQ-ABL1. SFPQ-ABL1 expression resulted in phosphorylation of proteins involved in RNA processing, metabolism and splicing, suggesting that SFPQ region of SFPQ-ABL1 also contributes to signalling. Conclusions: In this study, we have utilised phosphoproteomics for the unbiased identification of signalling nodes that are required for the function of different classes of ABL fusions. We have developed novel in vitro and in vivo models to further understand how these fusions function to drive leukaemia. Our data also suggests that ABL1 fusion partners play a role beyond dimerization and transphosphorylation of the kinase domains in oncogenic signalling, but further study is needed to establish the contribution to leukaemogenesis. Establishing signalling pathways that are critical to the function of rare ABL1 fusions may inform clinical approaches to treating this disease. Disclosures No relevant conflicts of interest to declare.

scholarly journals HNRNPH1 Is a Novel Regulator Of Cellular Proliferation and Disease Progression in Chronic Myeloid Leukemia

2021 ◽  
Vol 11 ◽  
Author(s):  
Menghan Liu ◽  
Lin Yang ◽  
Xiaojun Liu ◽  
Ziyuan Nie ◽  
Xiaoyan Zhang ◽  
...  
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Disease Progression ◽  
Myeloid Leukemia ◽  
Cellular Proliferation ◽  
Rna Binding ◽  
Rna Binding Proteins ◽  
Critical Role ◽  
Multiple Cancer

RNA binding proteins act as essential modulators in cancers by regulating biological cellular processes. Heterogeneous nuclear ribonucleoprotein H1 (HNRNPH1), as a key member of the heterogeneous nuclear ribonucleoproteins family, is frequently upregulated in multiple cancer cells and involved in tumorigenesis. However, the function of HNRNPH1 in chronic myeloid leukemia (CML) remains unclear. In the present study, we revealed that HNRNPH1 expression level was upregulated in CML patients and cell lines. Moreover, the higher level of HNRNPH1 was correlated with disease progression of CML. In vivo and in vitro experiments showed that knockdown of HNRNPH1 inhibited cell proliferation and promoted cell apoptosis in CML cells. Importantly, knockdown of HNRNPH1 in CML cells enhanced sensitivity to imatinib. Mechanically, HNRNPH1 could bind to the mRNA of PTPN6 and negatively regulated its expression. PTPN6 mediated the regulation between HNRNPH1 and PI3K/AKT activation. Furthermore, the HNRNPH1–PTPN6–PI3K/AKT axis played a critical role in CML tumorigenesis and development. The present study first investigated the deregulated HNRNPH1–PTPN6–PI3K/AKT axis moderated cell growth and apoptosis in CML cells, whereby targeting this pathway may be a therapeutic CML treatment.

scholarly journals Intracellular delivery of anti-BCR/ABL antibody by PLGA nanoparticles suppresses the oncogenesis of chronic myeloid leukemia cells

2021 ◽  
Vol 14 (1) ◽  
Author(s):  
Guoyun Jiang ◽  
Zhenglan Huang ◽  
Ying Yuan ◽  
Kun Tao ◽  
Wenli Feng
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Tyrosine Kinase ◽  
Myeloid Leukemia ◽  
Kinase Activity ◽  
Kinase Inhibitors ◽  
Fusion Gene ◽  
Intracellular Delivery ◽  
Tyrosine Kinase Activity

Abstract Background The pathogenesis of chronic myeloid leukemia (CML) is the formation of the BCR/ABL protein, which is encoded by the bcr/abl fusion gene, possessing abnormal tyrosine kinase activity. Despite the wide application of tyrosine kinase inhibitors (TKIs) in CML treatment, TKIs drug resistance or intolerance limits their further usage in a subset of patients. Furthermore, TKIs inhibit the tyrosine kinase activity of the BCR/ABL oncoprotein while failing to eliminate the pathologenic oncoprotein. To develop alternative strategies for CML treatment using therapeutic antibodies, and to address the issue that antibodies cannot pass through cell membranes, we have established a novel intracellular delivery of anti-BCR/ABL antibodies, which serves as a prerequisite for CML therapy. Methods Anti-BCR/ABL antibodies were encapsulated in poly(d, l-lactide-co-glycolide) nanoparticles (PLGA NPs) by a double emulsion method, and transferrin was labeled on the surface of the nanoparticles (Ab@Tf-Cou6-PLGA NPs). The characteristics of nanoparticles were measured by dynamic light scattering (DLS) and transmission electron microscopy (TEM). Cellular uptake of nanoparticles was measured by flow cytometry (FCM). The effect of nanoparticles on the apoptosis and proliferation of CML cells was testified by FCM and CCK-8 assay. In addition, the anti-cancer impact of nanoparticles was evaluated in mouse models of CML. Results The results demonstrated that the Ab@Tf-Cou6-PLGA NPs functioned as an intracellular deliverer of antibodies, and exhibited an excellent effect on degrading BCR/ABL oncoprotein in CML cells via the Trim-Away pathway. Treatment with Ab@Tf-Cou6-PLGA NPs inhibited the proliferation and induced the apoptosis of CML cells in vitro as well as impaired the oncogenesis ability of CML cells in vivo. Conclusions In conclusion, our study indicated that this approach achieved safe and efficient intracellular delivery of antibodies and degraded BCR/ABL oncoprotein via the Trim-Away pathway, which provides a promising therapeutic strategy for CML patients, particularly those with TKI resistance.

The Flt3 ITD Accelerates An Already Established Myeloid Leukemia and Alters Chemotherapy Response In Vitro and In Vivo in a p53 Dependent Manner.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 1719-1719
Author(s):  
Timothy Pardee ◽  
Johannes Zuber ◽  
Scott Lowe
Keyword(s):  
Myeloid Leukemia ◽  
Target Genes ◽  
Conflicts Of Interest ◽  
Disease Onset ◽  
High Dose ◽  
Chemotherapy Response ◽  
Dependent Manner ◽  
Response To Chemotherapy

Abstract Abstract 1719 Poster Board I-745 Acute myeloid leukemia (AML) is an aggressive disease with heterogeneous genetics and variable prognosis. The presence of an internal tandem duplication within the FLT3 gene (Flt3 ITD) is a marker for poor prognosis and has been linked to anthracycline resistance in cell lines and primary patient samples in vitro. The effect of this mutation on response to chemotherapy in vivo has not been examined and its effect on response to cytarabine is not known. In this study we use a genetically defined mouse model of AML to examine the effects of the Flt3 ITD on response to cytarabine and the anthracycline doxorubicin in vitro and in vivo. In vitro the Flt3 ITD conferred resistance to doxorubicin and the combination of doxorubicin and cytarabine but sensitivity to cytarabine alone in comparison to the identical leukemia without the Flt3 ITD. In vivo the presence of the Flt3 ITD provided an advantage in leukemic engraftment and accelerated disease onset. This advantage could be partially reversed by treatment of the animals with cytarabine but not by treatment with doxorubicin. Surprisingly, in vivo the Flt3 ITD conferred a marked increase in sensitivity to cytarabine when compared to the parental leukemia without this mutation. In contrast to the parental leukemia, the addition of doxorubicin to cytarabine provided no advantage over cytarabine alone. When the DNA damage response was assessed the presence of the Flt3 ITD resulted in an increase in the levels of p53 following treatment with either doxorubicin or cytarabine. Induction of the p53 target genes p21 and MDM2 was also increased. Surprisingly, the Flt3 ITD had no effect on disease onset or chemotherapy response in vitro or in vivo in the setting of p53 null AML. These data when taken together demonstrate that the Flt3 ITD confers a mixed sensitivity and resistance to standard chemotherapy and provides an engraftment advantage in a manner that depends on an intact p53 allele. This may at least in part explain the rarity of dual p53 null and Flt3 ITD positive AML. Furthermore, these data suggest that patients with Fl3 ITD positive AML may benefit more from treatment with high dose Ara-C then with combinations containing an anthracycline. Disclosures No relevant conflicts of interest to declare.

scholarly journals Bactericidal/Permeability-Increasing Protein Preeminently Mediates Clearance of Pseudomonas aeruginosa In Vivo via CD18-Dependent Phagocytosis

2021 ◽  
Vol 12 ◽  
Author(s):  
Jomkuan Theprungsirikul ◽  
Sladjana Skopelja-Gardner ◽  
Ashley S. Burns ◽  
Rachel M. Wierzbicki ◽  
William F. C. Rigby
Keyword(s):  
Pseudomonas Aeruginosa ◽  
Critical Role ◽  
Chronic Obstructive ◽  
Dependent Manner ◽  
Opsonic Activity ◽  
Obstructive Pulmonary Disease ◽  
Neutrophil Dysfunction ◽  
Chronic Lung Infection

Chronic Pseudomonas aeruginosa infection mysteriously occurs in the airways of patients with cystic fibrosis (CF), bronchiectasis (BE), and chronic obstructive pulmonary disease (COPD) in the absence of neutrophil dysfunction or neutropenia and is strongly associated with autoimmunity to bactericidal permeability-increasing protein (BPI). Here, we define a critical role for BPI in in vivo immunity against P. aeruginosa. Wild type and BPI-deficient (Bpi-/-) mice were infected with P. aeruginosa, and bacterial clearance, cell infiltrates, cytokine production, and in vivo phagocytosis were quantified. Bpi-/- mice exhibited a decreased ability to clear P. aeruginosa in vivo in concert with increased neutrophil counts and cytokine release. Bpi-/- neutrophils displayed decreased phagocytosis that was corrected by exogenous BPI in vitro. Exogenous BPI also enhanced clearance of P. aeruginosa in Bpi-/- mice in vivo by increasing P. aeruginosa uptake by neutrophils in a CD18-dependent manner. These data indicate that BPI plays an essential role in innate immunity against P. aeruginosa through its opsonic activity and suggest that perturbations in BPI levels or function may contribute to chronic lung infection with P. aeruginosa.

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