PPARs in Irradiation-Induced Gastrointestinal Toxicity

The use of radiation therapy to treat cancer inevitably involves exposure of normal tissues. Although the benefits of this treatment are well established, many patients experience distressing complications due to injury to normal tissue. These side effects are related to inflammatory processes, and they decrease therapeutic benefit by increasing the overall treatment time. Emerging evidence indicates that PPARs and their ligands are important in the modulation of immune and inflammatory reactions. This paper discusses the effects of abdominal irradiation on PPARs, their role and functions in irradiation toxicity, and the possibility of using their ligands for radioprotection

PPARs and Anticancer Therapies

Editoria

Le recepteur pancreatique de la bombesine. Analyse moleculaire et fonctionnelle

SIGLEINIST T 74096 / INIST-CNRS - Institut de l'Information Scientifique et TechniqueFRFranc

Réponse immunitaire induite par l irradiation colorectale (manipulation thérapeutique des toll like receptors )

L exposition aux rayonnements ionisants de la sphère abdomino-pelvienne est associée à une haute incidence de complications. Lors des cas les plus importants, l apparition d ulcérations peut entrainer le décès des patients en absence de lourds traitements. Dans ces cas, des essais cliniques sont réalisés avec des Cellules Souches Mésenchymateuses (CSM). Les radiothérapies abdomino-pelvienne peuvent provoquer à court et/ou long terme des effets délétères. Des études démontrent que l injection de motifs bactériens confère une radioprotection au niveau intestinal. Ils stimulent des récepteurs (Toll-Like-Receptors (TLR)) situés à la surface des cellules intestinales. Cette thèse a pour but de caractériser les effets sur l immunité et sur la réparation tissulaire de la stimulation des TLR dans un modèle d irradiation colorectale localisée à 20 Gy (effets aigues des radiothérapies) chez le rat. Puis de potentialiser les effets des CSM avec une adjonction de ligands de TLR lors d une irradiation colorectale localisée à 27 Gy (complications accidentelles). Ce travail a permis à 20 Gy, de montrer que la stimulation des TLR conduisait à améliorer l homéostasie (normalisation des lymphocytes T, induction de lymphocytes T régulateurs (Treg) et de macrophages anti-inflammatoire M2). Dans le modèle 27 Gy, l injection de ligand de TLR pré greffe de CSM permet une amélioration du climat immunitaire avec une diminution des cytokines pro-inflammatoires et l induction de Treg et M2. Ces modulations pourraient permettre une meilleure implantation et efficacité des CSM. Toutes les observations apportées montrent que la stimulation de l immunité est une approche pour limiter les dommages radio- induitsExposure of the abdomino-pelvic sphere to ionizing radiation is associated with a high incidence of complications. Radiation therapy may cause short and / or long-term harmful effects. In the most severe cases and in the absence of heavy treatments, the appearance of ulcers may induce the death of patients. Clinical trials are being conduced with Mesenchymal Stem Cells (MSC) to cure theses complications. Others studies indicate that the injection of bacterial motifs limits the radiotoxicity in the intestine. They stimulate receptors (Toll-Like- Receptors (TLR)) located on the surface of epithelial and intestinal immune cells. The first aim of this doctoral work is to characterize the effects of TLR stimulation on immunity and tissue repair using a model of localized colorectal irradiation at 20 Gy (acute effects of radiotherapy) on a rat. The thesis then aims to potentiate the effects of the MSC treatment when adding TLR ligands upon localized colorectal irradiation at 27 Gy (accidental complications). This work, using a 20 Gy exposure, show that TLR stimulation improves homeostasis (normalization of T cells, induction of regulatory T cells (Treg) and macrophages "anti-inflammatory" M2). On the 27 Gy colorectal model, the injection of TLR ligand before CSM transplant improves the immune climate by reducing pro-inflammatory cytokines and inducting Treg and M2 cells. These modulations could contribute to improving the implantation and effectiveness of CSM. The observations have all shown that the stimulation of immunity is an approach to minimize radiation-induced lesionsPARIS-BIUSJ-Biologie recherche (751052107) / SudocSudocFranceF

Acute and persisting Th2-like immune response after fractionated colorectal γ-irradiation

AIM: To investigate if an immune imbalance may account for the development and progression of chronic radiation enteritis. We analyzed the Th1/Th2 immune response profile early and 6 mo after fractionated colorectal irradiation

Systemically delivered adipose stromal vascular fraction mitigates radiation-induced gastrointestinal syndrome by immunomodulating the inflammatory response through a CD11b+ cell-dependent mechanism

International audienceBackground Stromal vascular fraction (SVF) treatment promoted the regeneration of the intestinal epithelium, limiting lethality in a mouse model of radiation-induced gastrointestinal syndrome (GIS). The SVF has a heterogeneous cell composition; the effects between SVF and the host intestinal immunity are still unknown. The specific role of the different cells contained in the SVF needs to be clarified. Monocytes-macrophages have a crucial role in repair and monocyte recruitment and activation are orchestrated by the chemokine receptors CX3CR1 and CCR2. Methods Mice exposed to abdominal radiation (18 Gy) received a single intravenous injection of SVF (2.5 × 10 6 cells), obtained by enzymatic digestion of inguinal fat tissue, on the day of irradiation. Intestinal immunity and regeneration were evaluated by flow cytometry, RT-PCR and histological analyses. Results Using flow cytometry, we showed that SVF treatment modulated intestinal monocyte differentiation at 7 days post-irradiation by very early increasing the CD11b + Ly6C + CCR2 + population in the intestine ileal mucosa and accelerating the phenotype modification to acquire CX3CR1 in order to finally restore the F4/80 + CX3CR1 + macrophage population. In CX3CR1-depleted mice, SVF treatment fails to mature the Ly6C − MCHII + CX3CR1 + population, leading to a macrophage population deficit associated with proinflammatory environment maintenance and defective intestinal repair; this impaired SVF efficiency on survival. Consistent with a CD11b + being involved in SVF-induced intestinal repair, we showed that SVF-depleted CD11b + treatment impaired F4/80 + CX3CR1 + macrophage pool restoration and caused loss of anti-inflammatory properties, abrogating stem cell compartment repair and survival. Conclusions These data showed that SVF treatment mitigates the GIS-involving immunomodulatory effect. Cooperation between the monocyte in SVF and the host monocyte defining the therapeutic properties of the SVF is necessary to guarantee the effective action of the SVF on the GIS

Stromal vascular fraction for the treatment of the radiation-induced gastrointestinal syndrome

International audienceAccidental or intentional radiation exposures have serious health consequences for exposed individuals and can affect a large number of people. Large volume irradiation at high irradiation doses induces multiple tissue lesions. The gastro-intestinal tract is particularly sensitive to irradiation and lethality. At dose more than 10 Gy results in diarrhea, dehydration, sepsis and intestinal bleeding with mortality within 10 post-exposure. Radiationinduced gastrointestinal syndrome (GIS) results from direct cytocidal effects on intestinal stem cells and crypt stroma impairing epithelial regeneration. Damaged intestinal epithelium significantly reduces the mucosal integrity and promotes systemic bacteria influx resulting in sepsis and death. Given the logistical hurdle and the urgency for treatment in large numbers of casualties, there is a tremendous need for effective therapeutic measures, even if implemented several days after radiation exposure. The stromal vascular fraction (SVF) derived from adipose tissue is an easily accessible source of cells with angiogenic, antiinflammatory, immunomodulatory, and regenerative properties. We examined whether SVF restores the irradiated intestinal cells niche and mitigates the GIS. At the day of abdominal irradiation (18Gy) mice were injected in systemic with SVF, obtained by enzymatic digestion of adipose tissue. Seven days post-irradiation, SVF treatment limited weight loss and inhibited intestinal permeability [1]. When injected before 24 hours post-irradiation, SVF limited the mortality. SVF has an anti-inflammatory effect in the intestine by repressing proinflammatory cytokines, accelerating the maturation of monocyte able to generate antiinflammatory macrophages. Immunohistological analyses of intestine showed that SVF treatment stimulated the regeneration of the epithelium by promoting numerous hyperproliferative zones. SVF restored the cell population in the intestinal stem cell compartment. The ex-vivo intestinal "organoid" model that mimics the clinical response confirmed that SVF treatment stimulated the intestinal stem cell compartment. With pleiotropic effects that contribute to limite radiation-induced lethality, SVF offers attractive prospects for the treatment of emergency GIS