Colony-Stimulating Factor-1 Promotes Kidney Growth and Repair via Alteration of Macrophage Responses

Colony-stimulating factor (CSF)-1 controls the survival, proliferation, and differentiation of macrophages, which are recognized as scavengers and agents of the innate and the acquired immune systems. Because of their plasticity, macrophages are endowed with many other essential roles during development and tissue homeostasis. We present evidence that CSF-1 plays an important trophic role in postnatal organ growth and kidney repair. Notably, the injection of CSF-1 postnatally enhanced kidney weight and volume and was associated with increased numbers of tissue macrophages. Moreover, CSF-1 promotes postnatal renal repair in mice after ischemia-reperfusion injury by recruiting and influencing macrophages toward a reparative state. CSF-1 treatment rapidly accelerated renal repair with tubular epithelial cell replacement, attenuation of interstitial fibrosis, and functional recovery. Analysis of macrophages from CSF-1-treated kidneys showed increased expression of insulin-like growth factor-1 and anti-inflammatory genes that are known CSF-1 targets. Taken together, these data suggest that CSF-1 is important in kidney growth and the promotion of endogenous repair and resolution of inflammatory injury.Macrophages are versatile cells that have been long recognized as immune effectors where their recruitment to sites of injury is a fundamental feature of inflammation. Although their role in host defense has been well documented, macrophages and their precursors are also important during embryogenesis, normal tissue maintenance, and postnatal organ repair.^1,2 Almost all developing organs contain a population of resident monocytes that infiltrate very early during organogenesis and persist throughout adult life.^3–6 In addition to their phagocytic capabilities during tissue remodeling-associated apoptosis,^5,7 fetal macrophages have many trophic effects that promote tissue and organ growth.^6,8,9Colony-stimulating factor (CSF)-1 controls the differentiation, proliferation, and survival of macrophages by binding to a high-affinity cell-surface tyrosine kinase receptor (CSF-1R), encoded by the c-fms proto-oncogene that is expressed on macrophages and their progenitors.⁶ CSF-1 is critical for both adult and embryonic macrophage development. This is manifested by multiple organ growth deficiencies observed in osteopetrotic (Csf1^op/Csf1^op) mice that have a spontaneous mutation in the csf-1 gene. These mice show growth restriction and developmental abnormalities of the bones, brain, and reproductive and endocrine organs,^10–13 a phenotype that can be rescued by injection of exogenous CSF-1 or insertion of a csf-1 transgene.^14–16In adult organs, there is considerable heterogeneity of monocytes and macrophages with distinct subsets defined by phenotype, function, and the differential expression of cell surface markers.^17–19 Subpopulations of macrophages directly contribute to wound healing and tissue repair, supporting the concept that some macrophage phenotypes can promote organ regeneration after a pro-inflammatory state of injury.²⁰ The concept of macrophage polarization states has emerged; the M1 “classically activated” pro-inflammatory cell type apparently opposed by an M2 “alternatively activated” immune regulatory macrophage.¹⁸ In general, these two states are thought to be analogous to the opposing T helper 1 and T helper 2 immune responses, although in both cases this model is probably too simplistic. Functionally, it is more likely that distinct subpopulations of macrophages may exist in the same tissue and play critical roles in both the injury and recovery phases of inflammatory scarring.²⁰Our previous study provided evidence that the addition of CSF-1 to a developing murine kidney promotes a growth and differentiation response that is accompanied by increased numbers of macrophages.³ Furthermore, with the use of expression profiling we demonstrated that fetal kidney, lung, and brain macrophages share a characteristic gene expression profile that includes the production of factors important in the suppression of inflammation and the promotion of proliferation.³ Embryonic macrophages appear to play a positive trophic role that may have parallel reparative functions in many adult tissues undergoing repair and cellular replacement.^1,20 A number of studies have suggested that infiltrating macrophages along with the trophic factors they release participate in tissue repair of the kidney,^20–22 brain,²³ skin,^24,25 lung,²⁶ liver,²⁷ heart,²⁸ gastrointestinal tract,^29,30 and skeletal muscle.^31,32 Indeed, the pleiotrophic roles for CSF-1 in reproduction, development of multiple organ systems, and maternal-fetal interactions during pregnancy by macrophage-mediated processes have also been well defined.^2,33,34To determine the physiological relevance of CSF-1 as a component of the mammalian growth regulatory axis, CSF-1 was administered to neonatal mice. We report that CSF-1 administration to newborn mice increased body weight and kidney weight and volume and was associated with increased numbers of macrophages. Our results also establish that CSF-1 injection into mice after ischemia-reperfusion (IR) injury promoted endogenous repair with characteristic rapid re-epithelialization of the damaged tubular epithelium, leading to functional recovery. Flow cytometric and gene expression analyses were used to delineate the macrophage profile present in the kidneys during the early and resolution phase of IR injury with and without CSF-1 therapy. We thus provide evidence that CSF-1 recruits macrophages to the reparative site and influences their phenotype, partly through an insulin-like growth factor (IGF)-1 signaling response. Therefore, macrophages under the stimulus of CSF-1 in an acute setting of renal disease markedly accelerate renal cell replacement and tissue remodeling while attenuating downstream interstitial extracellular matrix accumulation.     

Microglia/macrophages migrate through retinal epithelium barrier by a transcellular route in diabetic retinopathy: role of PKCζ in the Goto Kakizaki rat model

Diabetic retinopathy is associated with ocular inflammation, leading to retinal barrier breakdown, macular edema, and visual cell loss. We investigated the molecular mechanisms involved in microglia/macrophages trafficking in the retina and the role of protein kinase Cζ (PKCζ) in this process. Goto Kakizaki (GK) rats, a model for spontaneous type 2 diabetes were studied until 12 months of hyperglycemia. Up to 5 months, sparse microglia/macrophages were detected in the subretinal space, together with numerous pores in retinal pigment epithelial (RPE) cells, allowing inflammatory cell traffic between the retina and choroid. Intercellular adhesion molecule-1 (ICAM-1), caveolin-1 (CAV-1), and PKCζ were identified at the pore border. At 12 months of hyperglycemia, the significant reduction of pores density in RPE cell layer was associated with microglia/macrophages accumulation in the subretinal space together with vacuolization of RPE cells and disorganization of photoreceptors outer segments. The intraocular injection of a PKCζ inhibitor at 12 months reduced iNOS expression in microglia/macrophages and inhibited their migration through the retina, preventing their subretinal accumulation. We show here that a physiological transcellular pathway takes place through RPE cells and contributes to microglia/macrophages retinal trafficking. Chronic hyperglycemia causes alteration of this pathway and subsequent subretinal accumulation of activated microglia/macrophages.     

Comparative study of the metal accumulation in Hysterothalycium reliquens (nematode) and Paraphilometroides nemipteri (nematode) as compared with their doubly infected host,Nemipterus peronii (Notched threadfin bream)

In February 2013, forty-seven Notched threadfin bream, the Nemipterus peronii, were sampled from the eastern coastal waters of the South China Sea. The concentration of various elements, namely cadmium (Cd), chromium (Cr), copper (Cu), mercury (Hg), strontium (Sr), manganese (Mn), selenium (Se), Lead (Pb), nickel (Ni), aluminum (Al), arsenic (As), iron (Fe), and Zinc (Zn) were analyzed in the liver, muscle, and kidney organs of the host, as well as in their parasites Hysterothalycium reliquens (nematode) and the Paraphilometroides nemipteri (nematode), using inductively coupled plasma mass spectrometry (ICP-MS). The former group of parasites showed highest accumulation capacity for Cr, Cu, Fe, Mn, Se, Ni, and Zn while the latter group had high accumulation potential of As, Hg, Cd, Al, Pb, and Sr. The divergence in heavy-metal accumulation profiles of both nematodes is linked with the specificity of microhabitats, cuticle morphology, and interspecific competition. The outcome of this study indicates that both parasite models can be used for biomonitoring of metal pollution in marine ecosystems.     

Morphology and Properties of Novel Blends Prepared from Simultaneous In Situ Polymerization and Compatibilization of Macrocyclic Carbonates and Maleated Poly(propylene)

Summary: Nanoscale polymer blend morphologies, with a dispersed minor phase as small as 50 nm, have been prepared via the in situ polymerization of macrocyclic carbonates in the presence of a maleic anhydride poly(propylene) (mPP). This simple, versatile, low cost strategy successfully produced a well‐defined, stable two phase nanoscale morphology with a considerable improvement in the ultimate mechanical properties and strong resistance to hydrocarbon solvents such as methylene chloride. The effect of blend composition on the rate of polymerization of the macrocyclic carbonates was studied by considering the increase in torque during the mixing process in the batch mixer. The polymerization rate decreased considerably with increasing concentration of mPP in the blend due to the formation of graft copolymer of polycarbonate‐g‐poly(propylene) (PC‐g‐PP). The viscoelastic behavior of the pure polymer components was found to play no role in controlling the blend morphology and size of the dispersed nanoscale particles. The blend morphology could be controlled by the compatibilization of the blend components, possibly via in situ formation of a graft copolymer. In addition, the blend morphology was strongly influenced by the value of the rotation speed (rpm) or shear rate encountered during the processing of the blends, i.e., the larger the rpm value, the finer the observed blend morphology. Both DSC and DMA data showed evidence of partial miscibility of the polymer blend components. In addition, the DMA data confirmed a preferential dissolution of mPP in polycarbonate (PC) instead of dissolution of PC in mPP as evidenced by the shift of the α‐relaxation process of the PC‐rich phase to lower temperatures while the α‐relaxation process of the mPP was relatively unaffected regardless of the PC composition. The percentage of mPP dissolved in PC was evaluated from the reduction in the T_g value (obtained from DSC data) of PC in the blend using the Fox equation and was found to be consistent with the DMA data and preferential dissolution of mPP in PC.

STEM photograph of mPP/PC = 10/90 blend. The sample was prepared at 225 °C and 200 rpm.     

A common variant association study reveals novel susceptibility loci for low HDL‐cholesterol levels in ethnic Arabs

The genetic susceptibility to acquiring low high density lipoprotein‐cholesterol (LHDLC) levels is not completely elucidated yet. In this study, we performed a common variant association study for harboring this trait in ethnic Arabs. We employed the Affymetrix high‐density Axiom Genome‐Wide ASI Array (Asian population) providing a coverage of 598,000 single nucleotide variations (SNPs) to genotype 5495 individuals in a two‐phase study involving discovery and validation sets of experiments. The rs1800775 [1.31 (1.22–1.42); p = 3.41E‐12] in the CETP gene and rs359027 [1.26 (1.16–1.36); p = 2.55E‐08] in the LMCD1 gene were significantly associated with LHDLC levels. Furthermore, rs3104435 [1.26 (1.15–1.38); p = 1.19E‐06] at the MATN1 locus, rs9835344 [1.16 (1.08–1.26); p = 8.75E‐06] in the CNTN6 gene, rs1559997 [1.3 (1.14–1.47); p = 9.48E‐06] in the SDS gene and rs1670273 [1.2 (1.1–1.31); p = 4.81E‐06] in the DMN/SYNM gene exhibited suggestive association with the disorder. Seven other variants including rs1147169 in the PLCL1 gene, rs10248618 in the DNAH11, rs476155 in the GLIS3, rs7024300 in the ABCA1, intergenic rs10836699, rs11603691 in P2RX3 and rs750134 in CORO1C gene exhibited borderline protective properties. Validation and joint meta‐analysis resulted in rs1800775, rs3104435 and rs359027 retaining their predisposing properties, while rs10836699 and rs11603691 showed protective properties. Our data show several predisposing variants across the genome for LHDLC levels in ethnic Arabs.     

Thymoma with loss of keratin expression (and giant cells): a potential diagnostic pitfall

Due to its profound therapeutic consequences, the distinction between thymoma and T-lymphoblastic lymphoma in needle biopsies is one of the most challenging in mediastinal pathology. One essential diagnostic criterion favouring thymoma is the demonstration of increased numbers of keratin-positive epithelial cells by immunohistochemistry. Loss of keratin expression in neoplastic epithelial cells could lead to detrimental misdiagnoses. We here describe a series of 14 thymic epithelial tumours (11 type B2 and B3 thymomas, 3 thymic carcinomas) with loss of expression of one or more keratins. Cases were analysed for expression of various keratins and desmosomal proteins by immunohistochemistry and immunofluorescence and compared with 45 unselected type B thymomas and 24 thymic carcinomas arranged in a multitissue histological array. All 14 cases showed highly reduced expression of at least one keratin, three cases were completely negative for all keratins studied. Of the 14 cases, 13 showed strong nuclear expression of p63. Expression of desmosomal proteins was preserved, suggesting intact cell contact structures. Loss of expression of broad-spectrum-keratins and K19 was observed in 3 and 5 % of unselected thymomas and in 30 and 60 % of thymic carcinomas. A proportion of keratin-depleted thymomas contained giant cells, reminiscent of thymic nurse cells. Loss of keratin expression in type B2 and B3 thymomas is an important diagnostic pitfall in the differential diagnosis with T-lymphoblastic lymphoma and can be expected in 5 % of cases. A panel of epithelial markers including p63 is warranted to ensure correct diagnosis of keratin-negative mediastinal tumours.     

Lien social : maintien du lien social et familial pendant l’allogreffe de CSH

Objective

To set up the minimal conditions necessary to ensure that the social and familial network of the patient is preserved during the hospital stay for allogeneic hematopoïetic stem cell transplantation.

Material and methods

A national survey was conducted to increase knowledge about the conditions of hospital stay of adult and pediatric stem cell recipients. Then a multidisciplinary panel of health workers including doctors and nurses met to establish recommendations for maintaining the social and familial relationships optimally during the HSCT procedure.

Results

Practices and policies are very heterogeneous among the transplant centers. No consensus has been established and the literature data are scarce. The panel has thus established a list of recommendations to maintain optimal relationships between the patient and his relatives and friends during the hospital stay. The objective is to ensure a better acceptation of the isolation conditions and to facilitate the return home after D30.

Conclusion

Since there is no established scientific background for drastic isolation conditions, a multi-disciplinary approach in relationship with patients associations should allow softening of the procedures without impairing the quality of care.     

Broadband Dielectric Relaxation Spectroscopy of Functionalized Biobased Castor Oil Copolymer Thermosets

Novel biorenewable copolymer thermosets are successfully synthesized by the ring‐opening metathesis polymerization (ROMP) of norbornenyl‐functionalized castor oil (NCO) and norbornenyl‐functionalized castor oil alcohol (NCA) with controlled amounts of 0.8 and 1.8 norbornene rings per fatty acid chain, respectively. The NCO and NCA monomers are mixed in different concentrations and simultaneously polymerized via ROMP using Grubbs catalyst. Broadband dielectric relaxation spectroscopy (BDRS) is used to investigate the molecular dynamics of the fully cured copolymer thermosets over a wide range of frequencies (5 × 10^?2 to 0.5 × 10⁷ Hz) at different constant temperatures (?70 to 125 °C). Four phenomena, namely α‐, β‐, and γ‐relaxation processes and ionic conductivity are observed for all the measured samples.

     

Potential Influence of Interleukin-1 Receptor Antagonist Gene Polymorphism on Knee Osteoarthritis Risk

Objectives: Genes encoding for cytokines have been associated with susceptibility for joint osteoarthritis (OA) and interleukin (IL)-1 gene is supposed to be involved in the cartilage destruction process. In this regard, interleukin-1 receptor antagonist (IL-1RA) competing with IL-1 for binding to its receptor may act as an inhibitor of cartilage breakdown. We assessed the association of primary knee OA with IL-1RA region as a putative factor of susceptibility to knee OA in Egyptian patients. Design and methods: Eighty patients with primary knee OA and 40 aged-matched healthy controls were included into the study. DNA samples were used to study genotypes of IL-1RN gene by polymerase chain reaction (PCR) in both groups. Results: An increased frequency of the IL-1RN*1 and IL-1RN*2 alleles was found in OA patients relative to controls (60.5% vs. 39.5%, P = 0.039, 85.4% vs. 14.6%, P = 0.002, respectively) however, only the carriage rate of IL-1RN*2 allele was found to be significant when OA patients were compared to the controls. Significant higher frequencies of IL-1RN*1/*2 and IL-1RN*2/*2 genotypes in OA patients were observed as compared with controls. Both visual analogue scale (VAS) and radiographic score revealed significant correlation with both the allelic frequency and the carriage rate of IL-1RN*2 allele. Moreover, absolute frequency of IL-1RN*1/*2 genotype OA patients revealed severe VAS and high radiographic score. Conclusion: These results suggest that IL-1RN*2 allele represent a significant factor influencing the severity and course of knee OA; thereby supporting the potential role of IL-1 in the pathogenesis of this disease.     

Three Dimensional Active Contours for the Reconstruction of Abdominal Aortic Aneurysms

An aneurysm is a gradual and progressive ballooning of a blood vessel due to wall degeneration. Rupture of abdominal aortic aneurysm (AAA) constitutes a significant portion of deaths in the US. In this study, we describe a technique to reconstruct AAA geometry from CT images in an inexpensive and streamlined fashion. A 3D reconstruction technique was implemented with a GUI interface in MATLAB using the active contours technique. The lumen and the thrombus of the AAA were segmented individually in two separate protocols and were then joined together into a hybrid surface. This surface was then used to obtain the aortic wall. This method can deal with very poor contrast images where the aortic wall is indistinguishable from the surrounding features. Data obtained from the segmentation of image sets were smoothed in 3D using a Support Vector Machine technique. The segmentation method presented in this paper is inexpensive and has minimal user-dependency in reconstructing AAA geometry (lumen and wall) from patient image sets. The AAA model generated using this segmentation algorithm can be used to study a variety of biomechanical issues remaining in AAA biomechanics including stress estimation, endovascular stent-graft performance, and local drug delivery studies.