Dataset Information

Function of CSF1 and IL34 in Macrophage Homeostasis, Inflammation, and Cancer.

ABSTRACT: Colony-stimulating factor 1 (CSF1) and interleukin 34 (IL34) signal via the CSF1 receptor to regulate macrophage differentiation. Studies in IL34- or CSF1-deficient mice have revealed that IL34 function is limited to the central nervous system and skin during development. However, the roles of IL34 and CSF1 at homeostasis or in the context of inflammatory diseases or cancer in wild-type mice have not been clarified in vivo. By neutralizing CSF1 and/or IL34 in adult mice, we identified that they play important roles in macrophage differentiation, specifically in steady-state microglia, Langerhans cells, and kidney macrophages. In several inflammatory models, neutralization of both CSF1 and IL34 contributed to maximal disease protection. However, in a myeloid cell-rich tumor model, CSF1 but not IL34 was required for tumor-associated macrophage accumulation and immune homeostasis. Analysis of human inflammatory conditions reveals IL34 upregulation that may account for the protection requirement of IL34 blockade. Furthermore, evaluation of IL34 and CSF1 blockade treatment during Listeria infection reveals no substantial safety concerns. Thus, IL34 and CSF1 play non-redundant roles in macrophage differentiation, and therapeutic intervention targeting IL34 and/or CSF1 may provide an effective treatment in macrophage-driven immune-pathologies.

SUBMITTER: Lin W

PROVIDER: S-EPMC6736990 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

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Function of CSF1 and IL34 in Macrophage Homeostasis, Inflammation, and Cancer.

Lin WeiYu W Xu Daqi D Austin Cary D CD Caplazi Patrick P Senger Kate K Sun Yonglian Y Jeet Surinder S Young Judy J Delarosa Donnie D Suto Eric E Huang Zhiyu Z Zhang Juan J Yan Donghong D Corzo Cesar C Barck Kai K Rajan Sharmila S Looney Carrie C Gandham Vineela V Lesch Justin J Liang Wei-Ching WC Mai Elaine E Ngu Hai H Ratti Navneet N Chen Yongmei Y Misner Dinah D Lin Tori T Danilenko Dimitry D Katavolos Paula P Doudemont Estelle E Uppal Hirdesh H Eastham Jeffrey J Mak Judy J de Almeida Patricia E PE Bao Katherine K Hadadianpour Azadeh A Keir Mary M Carano Richard A D RAD Diehl Lauri L Xu Min M Wu Yan Y Weimer Robby M RM DeVoss Jason J Lee Wyne P WP Balazs Mercedesz M Walsh Kevin K Alatsis Kathila R KR Martin Flavius F Zarrin Ali A AA

Frontiers in immunology 20190904

Colony-stimulating factor 1 (CSF1) and interleukin 34 (IL34) signal <i>via</i> the CSF1 receptor to regulate macrophage differentiation. Studies in IL34- or CSF1-deficient mice have revealed that IL34 function is limited to the central nervous system and skin during development. However, the roles of IL34 and CSF1 at homeostasis or in the context of inflammatory diseases or cancer in wild-type mice have not been clarified <i>in vivo</i>. By neutralizing CSF1 and/or IL34 in adult mice, we identif ...[more]

PMID: 31552020

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Project description:UnlabelledAspergillus fumigatus, an opportunistic fungal pathogen, spreads in the environment by releasing numerous conidia that are capable of reaching the small alveolar airways of mammalian hosts. In otherwise healthy individuals, macrophages are responsible for rapidly phagocytosing and eliminating these conidia, effectively curbing their germination and consequent invasion of pulmonary tissue. However, under some circumstances, the fungus evades phagocyte-mediated immunity and persists in the respiratory tree. Here, we report thatA. fumigatusescapes macrophage recognition by strategically targeting phosphatidylinositol 3,4,5-trisphosphate [PtdIns(3,4,5)P3] metabolism through gliotoxin, a potent immunosuppressive mycotoxin. Time-lapse microscopy revealed that, in response to the toxin, macrophages cease to ruffle, undergo abrupt membrane retraction, and fail to phagocytose large targets effectively. Gliotoxin was found to prevent integrin activation and interfere with actin dynamics, both of which are instrumental for phagocytosis; similar effects were noted in immortalized and primary phagocytes. Detailed studies of the underlying molecular mechanisms of toxicity revealed that inhibition of phagocytosis is attributable to impaired accumulation of PtdIns(3,4,5)P3and the associated dysregulation of downstream effectors, including Rac and/or Cdc42. Strikingly, in response to the diacylglycerol mimetic phorbol 12-myristate 13-acetate, gliotoxin-treated macrophages reactivate beta integrins, reestablish actin dynamics, and regain phagocytic capacity, despite the overt absence of plasmalemmal PtdIns(3,4,5)P3 Together, our findings identify phosphoinositide metabolism as a critical upstream target of gliotoxin and also indicate that increased diacylglycerol levels can bypass the requirement for PtdIns(3,4,5)P3signaling during membrane ruffling and phagocytosis.ImportanceAspergillus fumigatusis the most frequent cause of human infections in theAspergillusgenus. In immunocompromised populations, invasive aspergillosis (IA) is associated with a mortality rate of up to 90%, and current antifungal therapies have failed to prevent or reverse the infection. Therefore, a deeper understanding of the interactions betweenA. fumigatusand its host is required. In healthy humans, alveolar macrophages can ingest and eliminate fungal spores, thus limiting their germination into mycotoxin-producing hyphae. Our studies reveal that gliotoxin-the most abundantAspergillusmycotoxin-undermines the ability of phagocytes to carry out their protective functions. By targeting PtdIns(3,4,5)P3signaling and downregulating phagocytic immune defenses, the toxin could also exacerbate polymicrobial infections. Notably, we were able to reverse gliotoxin toxicity by addition of diacylglycerol analogues, which may provide the basis for therapeutic interventions.

Dataset Information

Function of CSF1 and IL34 in Macrophage Homeostasis, Inflammation, and Cancer.

Publications

Function of CSF1 and IL34 in Macrophage Homeostasis, Inflammation, and Cancer.

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