scholarly journals Tumor conditions induce bone marrow expansion of granulocytic, but not monocytic, immunosuppressive leukocytes with increased CXCR2 expression in mice

2017 ◽  
Vol 48 (3) ◽  
pp. 532-542 ◽  
Author(s):  
Zhen Bian ◽  
Lei Shi ◽  
Mahathi Venkataramani ◽  
Ahmed Mansour Abdelaal ◽  
Courtney Culpepper ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Cxcr2 Expression ◽  
Marrow Expansion

Haemoglobinopathies

2013 ◽  
pp. 1466-1470
Author(s):  
David Rees
Keyword(s):  
Bone Marrow ◽  
Sickle Cell Disease ◽  
Sickle Cell ◽  
Lupus Erythematosus ◽  
Single Gene ◽  
Globin Genes ◽  
Globin Chain ◽  
Cell Disease ◽  
Chain Synthesis ◽  
Marrow Expansion

Inherited abnormalities of the globin genes are the commonest single-gene disorders in the world and fall into two main groups: thalassaemias and sickle cell disease. Thalassaemias are due to quantitative defects in globin chain synthesis which cause variable anaemia and ineffective erythropoiesis. Thalassaemia was initially thought to be a disease of the bones due to uncontrolled bone marrow expansion causing bony distortion, although this is now unusual with appropriate blood transfusions. Osteopenia, often severe, is a feature of most patients with thalassaemia major and intermedia, caused by bone marrow expansion, iron overload, endocrinopathy, and iron chelation. Treatment with bisphosphonates is generally recommended. Other rheumatological manifestations include arthropathy associated with the use of the iron chelator deferiprone. Sickle cell disease involves a group of conditions caused by polymerization of the abnormal -globin chain, resulting in abnormal erythrocytes which cause vaso-occlusion, vasculopathy, and ischaemic tissue damage. The characteristic symptom is acute bone pain caused by vaso-occlusion; typical episodes require treatment with opiate analgesia and resolve spontaneously by 5 days with no lasting bone damage. The frequency of acute episodes varies widely between patients. The incidence of osteomyelitis is increased, particularly with salmonella, although it is much rarer than acute vaso-occlusion. Avascular necrosis can affect the hips, and less commonly the shoulders and knees. Coincidental rheumatological disease sometimes complicates the condition, particularly systemic lupus erythematosus (SLE) which is more prevalent in populations at increased risk of sickle cell disease.

Haemoglobinopathies

2013 ◽  
Author(s):  
David Rees
Keyword(s):  
Bone Marrow ◽  
Sickle Cell Disease ◽  
Sickle Cell ◽  
Lupus Erythematosus ◽  
Single Gene ◽  
Globin Genes ◽  
Globin Chain ◽  
Cell Disease ◽  
Increased Risk ◽  
Marrow Expansion

Inherited abnormalities of the globin genes are the commonest single-gene disorders in the world and fall into two main groups: thalassaemias and sickle cell disease. Thalassaemias are due to quantitative defects in globin chain synthesis which cause variable anaemia and ineffective erythropoiesis. Thalassaemia was initially thought to be a disease of the bones due to uncontrolled bone marrow expansion causing bony distortion, although this is now unusual with appropriate blood transfusions. Osteopenia, often severe, is a feature of most patients with thalassaemia major and intermedia, caused by bone marrow expansion, iron overload, endocrinopathy, and iron chelation. Treatment with bisphosphonates is generally recommended. Other rheumatological manifestations include arthropathy associated with the use of the iron chelator deferiprone. Sickle cell disease involves a group of conditions caused by polymerization of the abnormal -globin chain, resulting in abnormal erythrocytes which cause vaso-occlusion, vasculopathy, and ischaemic tissue damage. The characteristic symptom is acute bone pain caused by vaso-occlusion; typical episodes require treatment with opiate analgesia and resolve spontaneously by 5 days with no lasting bone damage. The frequency of acute episodes varies widely between patients. The incidence of osteomyelitis is increased, particularly with salmonella, although it is much rarer than acute vaso-occlusion. Avascular necrosis can affect the hips, and less commonly the shoulders and knees. Coincidental rheumatological disease sometimes complicates the condition, particularly systemic lupus erythematosus (SLE) which is more prevalent in populations at increased risk of sickle cell disease.

Haemoglobinopathies

2016 ◽  
Author(s):  
David Rees
Keyword(s):  
Bone Marrow ◽  
Sickle Cell Disease ◽  
Sickle Cell ◽  
Lupus Erythematosus ◽  
Single Gene ◽  
Globin Genes ◽  
Globin Chain ◽  
Cell Disease ◽  
Increased Risk ◽  
Marrow Expansion

Inherited abnormalities of the globin genes are the commonest single-gene disorders in the world and fall into two main groups: thalassaemias and sickle cell disease. Thalassaemias are due to quantitative defects in globin chain synthesis which cause variable anaemia and ineffective erythropoiesis. Thalassaemia was initially thought to be a disease of the bones due to uncontrolled bone marrow expansion causing bony distortion, although this is now unusual with appropriate blood transfusions. Osteopenia, often severe, is a feature of most patients with thalassaemia major and intermedia, caused by bone marrow expansion, iron overload, endocrinopathy, and iron chelation. Treatment with bisphosphonates is generally recommended. Other rheumatological manifestations include arthropathy associated with the use of the iron chelator deferiprone. Sickle cell disease involves a group of conditions caused by polymerization of the abnormal -globin chain, resulting in abnormal erythrocytes which cause vaso-occlusion, vasculopathy, and ischaemic tissue damage. The characteristic symptom is acute bone pain caused by vaso-occlusion; typical episodes require treatment with opiate analgesia and resolve spontaneously by 5 days with no lasting bone damage. The frequency of acute episodes varies widely between patients. The incidence of osteomyelitis is increased, particularly with salmonella, although it is much rarer than acute vaso-occlusion. Avascular necrosis can affect the hips, and less commonly the shoulders and knees. Coincidental rheumatological disease sometimes complicates the condition, particularly systemic lupus erythematosus (SLE) which is more prevalent in populations at increased risk of sickle cell disease.

Photopenic Lesions in Bone Marrow Scintigraphy Using Technetium-99m Labeled Antigranulocyte Antibody without Known Tumour

1999 ◽  
Vol 38 (03) ◽  
pp. 85-89 ◽  
Author(s):  
M. Reinhardt ◽  
E. Nitzsche ◽  
E. Moser ◽  
Th. Krause
Keyword(s):  
Bone Marrow ◽  
Unknown Origin ◽  
Axial Skeleton ◽  
Tracer Uptake ◽  
Lower Limbs ◽  
Whole Body ◽  
Bone Marrow Scintigraphy ◽  
Age Related ◽  
Defect Pattern ◽  
Marrow Expansion

Summary Aim: The purpose of this study was to elucidate the frequency of photopenic lesions in patients without known tumour disease by using bone marrow scintigraphy with Tc-99m labeled anti-NCA-95. Methods: Whole body immunoscintigraphy (IS) was performed in 141 consecutive patients with fever of unknown origin. The age ranged between 20 and 88 years with a mean age of 57 years. None of the patients had known tumour disease. Scans were evaluated with respect to photopenic lesions and to bone marrow distribution. Results: IS showed bone marrow defects in the axial skeleton in 16 patients (11 %). With the help of the typical scintigraphic defect pattern, the cause of the lesions was clearly identified as degenerative changes in four patients and in one patient as due to prior sternotomy. In the remaining 11 patients the origin of the defects became evident when the case history or additional imaging was consulted. The mean age of these 16 patients was 69 years ranging from 50 to 88 years. There was an age-related frequency of defects. 10% of the patients from 50 to 59 years showed defects, 60-69 years 9%, 70-79 years 30%, and 33% of the patients from 80 to 89 years had defects. IS was not hampered by tracer uptake to liver or spleen in 93 patients. Left caudal ribs were obscured in 48 patients with intense tracer uptake to the spleen. No or markedly reduced tracer uptake was found in caput humeri and caput femori in 94 and 82 patients, respectively. Patchy tracer uptake to the bone marrow of the limbs was seen in 13/62 patients showing marrow expansion in the lower limbs and 14/55 with marrow expansion in the upper limbs. The patchy pattern was asymmetric in 12 of these patients. Conclusion: The results of the present study reveal that using Tc-99m NCA-95, photopenic lesions of the bone marrow are rarely seen in patients without known malignant disease. The occurrence of benign lesions is age-related. The benign cause of the lesion was obvious from location and pattern of the lesion in about 30% of the cases. Evaluation of lesions in the upper and lower limbs may be hindered due to physiological variation of marrow distribution. Nevertheless, IS appears to be well-suited for the detection and localization of bone marrow metastases.

Zoledronic Acid Increases Bone Mineral Density in Patients with Thalassemia Intermedia-Induced Osteoporosis Regardless of the Incessant Bone Marrow Expansion.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 3813-3813
Author(s):  
Ersi Voskaridou ◽  
Dimitrios Christoulas ◽  
Lito Antoniadou ◽  
Panagiotis Tsaftaridis ◽  
Eleni Plata ◽  
...  
Keyword(s):  
Bone Mineral Density ◽  
Bone Marrow ◽  
Placebo Group ◽  
Zoledronic Acid ◽  
Bone Loss ◽  
Bone Pain ◽  
Bone Remodelling ◽  
Erythropoietic Activity ◽  
Mineral Density ◽  
Marrow Expansion

Abstract Osteoporosis represents an important cause of morbidity in adult patients with thalassemia. Its pathogenesis is multifactorial, and includes mainly bone marrow expansion, endocrine dysfunction and iron overload. Patients with thalassaemia intermedia (TI) seem to have a more expanded bone marrow with pressure on cortical bone, which causes pain and bone loss in several cases. The measurement of soluble transferrin receptor (sTfR) and erythropoietin (Epo) in the serum is considered as accurate marker of erythropoietic activity in thalassemia. Bisphosphonates are potent inhibitors of osteoclast activity and have been used for the management of thalassemia-induced osteoporosis. The aim of this study was to evaluate the effect of zoledronic acid, the most potent aminobisphosphonate, on bone mineral density (BMD) of patients with TI and explore possible correlations with bone marrow expansion and erythropoietic activity. Thirty-five patients with TI and osteopenia or osteoporosis (13M/22F, median age 45 years) were evaluated. Twenty-three were randomized to receive zoledronic acid, 4 mg, IV, every 3 months (n=12) or every 6 months (n=11) for one year, while 12 patients received placebo every 3 months. There was no difference in terms of the presence of gonadal dysfunction between the three studied groups. BMD of the lumbar spine (L), femoral neck and forearm was determined in all patients, using DEXA, before and 12 months after treatment. Bone marrow expansion was assessed by the measurement of sTfR and Epo serum levels, using an ELISA methodology (R&D Systems, Minneapolis, MN, USA), before and 12 months post zoledronic acid or placebo administration. In all patients markers of bone remodelling, such as C-telopeptide of collagen type-I (CTX) and bone specific alkaline phosphatase (bALP) were also measured by ELISA (Nordic Bioscience Diagnostics, Herlev, Denmark, and Quidel, San Diego, CA, USA, respectively). Patients were asked to quantify their degree of bone pain on Huskisson’s visual analogue scale and the McGill-Melzack scoring system before and 12 months post-therapy. All patients had increased values of sTfR, Epo, CTX, and bALP compared with 40 controls of similar age and gender (p<0.001). Patients who received zoledronic acid showed a significant increase in their L-BMD (p=0.01), which was accompanied by a dramatic reduction in CTX and bALP values ((p<0.001). There was no difference in terms of L-BMD changes between zoledronic acid groups. Placebo group showed an aggravation of L-BMD (p=0.041) and markers of bone remodelling at 12 months. No other changes were observed in the BMD of other sites. Zoledronic acid reduced bone pain, which remained stable in placebo group during the study period. There was only weak correlation between baseline sTfR levels and L-BMD, while there was no correlation between Epo or hemolytic parameters (indirect bilirubin, reticulocytes counts, and LDH) with BMD of all studied sites. Serum sTfR and Epo values showed a significant elevation after 12 months of therapy in all studied groups (p<0.01, p<0.02, and p<0.01, respectively); this elevation was irrespective of the L-BMD changes. This study suggests that the increase of BMD produced by zoledronic acid in TI is irrespective of the continuous increase of bone marrow expansion, which is considered a major cause of bone loss in this hemoglobinopathy.

Bone Marrow Iron Concentration as a Marker of Iron Accumulation and Marrow Expansion in Patients with Beta Thalassemia Major.

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 1852-1852
Author(s):  
Paola Polchi ◽  
Rossella Palmieri ◽  
Marco Andreani ◽  
Javid Gaziev ◽  
Cecilia Alfieri ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Iron Content ◽  
Iron Concentration ◽  
Iron Chelation ◽  
Thalassemia Major ◽  
Beta Thalassemia ◽  
H63d Mutation ◽  
Class 1 ◽  
Bone Marrow Iron ◽  
Marrow Expansion

Abstract Liver iron concentration (LIC) is a known and accurate marker of iron accumulation and is widely utilized to monitor iron chelation therapy in multiply transfused patients with Beta thalassemia major. Iron concentration in the bone marrow has not been studied and reported before. We utilized atomic absorption spectrophotometry to measure the iron content of marrow biopsy (BIC) in 102 thalassemia patients in various phase of treatment, 74 of them during the course of the disease and 28 patients after successful allogeneic marrow transplant. We observed BIC values below 0.5 mg/g dry weight in 7 healthy donors used as controls. Mean and median BIC were 4.67 and 2.70 (range 0.05 – 59.9) mg/g dw, in 101 valuable patients. Bone Marrow iron concentration (BIC) was calculated at the same time of LIC for each patient and a ratio LIC/BIC was generated. LIC/BIC ratio below 3, ratio between 3 and 10, and above 10 identified three categories of patients each with significant linear correlation between LIC and BIC (0.74; 0.76; 0.81 respectively). Twenty eight patients were in the first category, 48 in the second, and 25 in the third. Mean BIC was 9.47, 3.7, 1.2 mg/g dw and mean LIC was 12.7, 19.6, 22.3 mg/g dw respectively for CAT1, CAT2 and CAT3. Patients were also classified in class of risk for transplant, based on hepatomegaly, presence of liver fibrosis and history of regular or irregular iron chelation. BIC was higher in class 3 patients and in the irregularly chelated patients. Patients in class 1 were prevalently in CAT1 or 2, patients in class 3 were prevalently in CAT2 or 3. BIC value in each of the 3 categories correlated significantly with the whole body iron (WBI) amount, and WBI was significantly different in the three categories being lower in CAT1, that have higher BIC ( 3927 mg; 5894 mg, 7030 mg in CAT1, 2 and 3; p 0.01). Iron chelation quality (regular vs irregular) correlated with BIC value and with BIC category, majority of regularly chelated patients were in the Category 1 vs Category 2 or 3 (p 0.01). Patients before transplant were prevalently in CAT1 and 2, while those post transplant were mostly in CAT3, twelve patients that were studied both before and after transplant, changed from cat 1 to 2 or from cat 2 to 3. Their BIC changed significantly decreasing after BMT (median BIC was 7.8 before transplant and 2.25 after, p=0.002) To investigate the role of genetic hemochromatosis mutations, H63D region and Hamp region in 63 patients were also studied. Mean BIC was 3.08 in 16 patients with H63D mutation compared to 5.59 in those without mutation, and 11/16 had BIC below the median, p=0.03. Significantly more patients with H63D mutation were in CAT3 (p 0.02). Apparently H63D mutation favours accumulation of iron in the body, that was higher in CAT3, but participate also to lowering utilization of introduced iron. In conclusion, patients in category 1 had lower LIC and higher BIC, comprehended 50% of the patients in class 1 of risk, and 45% of the regularly chelated patients. On the contrary, majority of patients post transplant independently of having or not performed an iron removal program were in CAT3. We can draw conclusion that BIC related categories, as described here, give information on the balance between accumulation and utilization of iron. Patients belonging to BIC-Cat 1 correspond to patients that have been treated adequately and with lower iron body burden, better chelation history. They have higher BIC value and lower LIC value. They also are in pre-transplant phase, with active beta-thalassemia, when ineffective erythropoiesis and marrow expansion are more prominent. Further studies will be necessary to confirm the association of marrow iron content with the marrow functionality and expansion.

scholarly journals Whole Transcriptome Sequencing Identifies Novel Pathways Associated with Paroxysmal Nocturnal Hemoglobinuria- Increased CXCR2 Expression in PNH Granulocytes

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 3608-3608
Author(s):  
Kohei Hosokawa ◽  
Sachiko Kajigaya ◽  
Keyvan Keyvanfar ◽  
Danielle M. Townsley ◽  
Bogdan Dumitriu ◽  
...  
Keyword(s):  
Stem Cells ◽  
Bone Marrow ◽  
Flow Cytometry ◽  
Hematopoietic Stem Cells ◽  
Research Funding ◽  
Lymphoid Cells ◽  
Hematopoietic Stem ◽  
Expression Levels ◽  
Cxcr2 Expression ◽  
Healthy Donors

Abstract Background. Paroxysmal nocturnal hemoglobinuria (PNH) is an acquired clonal disorder that arises from hematopoietic stem cells (HSCs). PNH is caused by a somatic mutation in the X-linked phosphatidylinositol glycan class A gene (PIG-A), responsible for a deficiency in glycosyl phosphatidylinositol-anchored proteins (GPI-APs). PNH is a clonal disease that originates from HSCs, as the originating PIGA mutation is present in cells of multiple lineages, including myeloid, erythroid, and lymphoid cells. However, a critical question regarding PNH that has yet to be fully explained despite several decades of research is the mechanism responsible for clonal expansion of PIGA -mutant cells in bone marrow failure. Using RNA-seq, we identify pathways, coding and non-coding RNA transcripts, splice variants, or single nucleotide variants and other alterations that may relate to the selective advantage of PNH clone. Method. Blood samples were obtained after informed consent from patients with 14 PNH and 18 age-matched healthy donors. From PNH patients and healthy donors, 4 samples were used for RNA sequencing 6 samples were used for validation by flow cytometry. The liquid FLAER method was used for the detection of PNH-type granulocytes. For RNA extraction, granulocytes were sorted for CD11b+ FLAER+ granulocytes, CD11b+ FLAER- granulocytes. For bone marrow staining, cells not expressing lineage markers were separated into five subpopulations: Long-term hematopoietic stem cells (LT-HSC; Lin- CD34+ CD38- CD90+), short-term hematopoietic stem cells (ST-HSC; Lin- CD34+ CD38- CD90-), common myeloid progenitors (CMP; Lin- CD34+ CD38+ CD123+ CD45RA-), granulocyte-monocyte progenitors (GMP; Lin- CD34+ CD38+ CD123+ CD45RA+) and megakaryocyte-erythrocyte progenitors (MEP; Lin- CD34+ CD38+ CD123- CD45RA-). Results and Discussion. First, RNA expression levels in CD11b+ FLAER+ and CD11b+ FLAER- populations of PNH patients were analyzed using RNA sequencing. Expression levels of 7 mRNAs (CSF2RB, ACSL1, FCGR3B, IL1RN, CXCR2, TREM1, and TNFRSR10C) were significantly upregulated (> 3 FC, P < 0.01) in CD11b+ FLAER- cells of PNH patients compared with CD11b+ FLAER+ cells. To validate the differential expression observed in GPI-AP- granulocytes from PNH patients, protein expression levels of CSF2RB, FCGR3B, CXCR2, TREM1, and TNFRSF10C were assessed by flow cytometry. In CD11b+ FLAER- granulocytes of 6 PNH patients, increased expression of CXCR2 was validated, whereas decreased expression of FCGRB and TNFRSF10C were validated compared with CD11b+ FLAER+ granulocytes and that of healthy controls. Low expression FCGRB and TNFRSR10C in CD11b+ FLAER- granulocytes were considered to be reasonable, as these were GPI-APs. Next, we examined whether increased CXCR2 expression in PNH-type cells was validated in different peripheral blood cell populations. Increased CXCR2 expression in PNH-type cells was confirmed in granulocyte and monocyte populations, not in T cell or B cell population. We checked the expression levels of CXCR1 and CXCR2, which are closely related receptors that recognize CXC chemokines. CXCR2 expression was significantly different between normal and PNH-type cells in granulocytes and monocytes, and CXCR1 expression was significant only for granulocytes. To address the difference of CXCR2 expression levels between normal and PNH-type cells in more undifferentiated cells, we next examined the CXCR2 expression levels in bone marrow hematopoietic stem cells. Expression of CXCR2 was weakly expressed in hematopoietic stem cells and progenitors, both in normal and PNH-type cells, suggesting that difference of CXCR2 expression between normal and PNH-type cells is evident only in differentiated myeloid cells, not in hematopoietic stem cells or lymphoid cells. Conclusion. We provide evidence for increased expression of CXCR2 in PNH-type granulcoytes and monocytes by RNA-seq and flow cytometry. The differential expression of CXCR2 might partly explain the dominance of PNH clones in myeloid cells in patients. CXCR2 is an adverse prognostic factor in MDS/AML and is a potential therapeutic target against immature leukemic stem cell-enriched cell fractions in MDS and AML (Schinke C, et al, Blood, 2015). Understanding the mechanism of increased CXCR2 expression in PNH-type cells may offer new therapeutic strategies and novel mechanistic insight into the pathophysiology of PNH. Disclosures Townsley: Novartis: Research Funding; GSK: Research Funding. Dumitriu:Novartis: Research Funding; GSK: Research Funding. Young:Novartis: Research Funding; GSK: Research Funding.

Knochenmarkveränderungen bei Patienten mit Schilddrüsenkarzinom

1991 ◽  
Vol 30 (06) ◽  
pp. 272-278 ◽  
Author(s):  
A. Linden ◽  
Ruth Weiß ◽  
Kamilla Smolarz ◽  
M. Jungehülsing ◽  
P. Theissen ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Thyroid Carcinoma ◽  
Radioiodine Therapy ◽  
Tnm Staging ◽  
Imaging Results ◽  
Bone Marrow Imaging ◽  
Thyroglobulin Level ◽  
Metastatic Involvement ◽  
Hematological Changes ◽  
Marrow Expansion

In 62 patients with thyroid carcinoma 79 MRI bone marrow examinations and 48 bone marrow scintigraphies were recorded before or following radioiodine therapy, to study the extent of bone marrow expansion. The results of both methods were the same. In 34/79 investigations normal findings were seen, in 18 the bone marrow expanded to the middle third and in 26 to the distal third of the femur. One patient showed bone marrow expansion to the tibia. These results were compared with the following data: histology of tumor, TNM- staging, time passed since thyroidectomy, accumulated doses of radioiodine therapy, results of131I scintigraphy, hematological changes, thyroglobulin level, age and sex. No significant correlations were found between these and the bone marrow imaging results. Bone marrow changes in patients before radioiodine therapy were similar to those in patients treated with up to 48 GBq 131I. Blind biopsy of the posterior iliac crest in five patients showed slightly pathological reactive changes. In only 2/17 follow-up studies an increase of bone marrow expansion was seen. In 8 patients localized findings indicating malignant infiltration were observed. In 4/8 patients metastases of thyroid carcinoma were known or confirmed by pathological radioiodine uptake and in 2/8 metastatic involvement was assumed because of an increased thyroglobulin level.

scholarly journals Leptin Receptor q223r Polymorphism Influences Clostridioides difficile Infection-Induced Neutrophil CXCR2 Expression in an Interleukin-1β Dependent Manner

2021 ◽  
Vol 11 ◽  
Author(s):  
Olivia Horrigan ◽  
Shinsmon Jose ◽  
Anindita Mukherjee ◽  
Divya Sharma ◽  
Alexander Huber ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Leptin Receptor ◽  
Innate Immune ◽  
Dependent Manner ◽  
Biological Mechanisms ◽  
Colonic Tissue ◽  
Host Genetics ◽  
Cxcr2 Expression ◽  
Clostridioides Difficile ◽  
Blood Neutrophils

Neutrophils are key first-responders in the innate immune response to C. difficile infection (CDI) and play a central role in disease pathogenesis. Studies have clearly shown that tissue neutrophil numbers need to be tightly regulated for optimal CDI outcomes: while excessive colonic neutrophilia is associated with severe CDI, neutrophil depletion also results in worse outcomes. However, the biological mechanisms that control CDI-induced neutrophilia remain poorly defined. C-X-C chemokine receptor 2 (CXCR2) is a chemotactic receptor that is critical in neutrophil mobilization from bone marrow to blood and tissue sites. We have previously reported that a single nucleotide polymorphism (SNP) in leptin receptor (LEPR), present in up to 50% of people, influenced CDI-induced neutrophil CXCR2 expression and tissue neutrophilia. Homozygosity for mutant LEPR (i.e. RR genotype) was associated with higher CXCR2 expression and more tissue neutrophils. Here, we investigated the biological mechanisms that regulate neutrophil CXCR2 expression after CDI, and the influence of host genetics on this process. Our data reveal that: a) CXCR2 plays a key role in CDI-induced neutrophil extravasation from blood to colonic tissue; b) plasma from C. difficile-infected mice upregulated CXCR2 on bone marrow neutrophils; c) plasma from C. difficile-infected RR mice induced a higher magnitude of CXCR2 upregulation and had more IL-1β; and d) IL-1β neutralization reduced CXCR2 expression on bone marrow and blood neutrophils and their subsequent accrual to colonic tissue. In sum, our data indicate that IL-1β is a key molecular mediator that communicates between gastro-intestinal tract (i.e. site of CDI) and bone marrow (i.e. primary neutrophil reservoir) and regulates the intensity of CDI-induced tissue neutrophilia by modulating CXCR2 expression. Further, our studies highlight the importance of host genetics in affecting these innate immune responses and provide novel insights into the mechanisms by which a common SNP influences CDI-induced neutrophilia.

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