Cytokine overproduction and crosslinker hypersensitivity are unlinked in Fanconi anemia macrophages
| Autor: | Nathaniel Jillette, Kathy Chin, R. Keaney Rathbun, Muhsen Al-Dhalimy, Anupriya Agarwal, Laura E. Hays, Michael R. Garbati, Grover C. Bagby, Amy E. Hanlon Newell, Susan B. Olson |
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| Jazyk: | angličtina |
| Rok vydání: | 2015 |
| Předmět: |
0301 basic medicine
congenital hereditary and neonatal diseases and abnormalities Fanconi anemia complementation group C DNA damage medicine.medical_treatment Mitomycin Immunology Biology Proinflammatory cytokine Histones 03 medical and health sciences Mice Fanconi anemia hemic and lymphatic diseases medicine Immunology and Allergy Macrophage Animals Humans Cells Cultured Tumor Necrosis Factor-alpha Inflammation Extracellular Mediators & Effector Molecules Macrophages Fanconi Anemia Complementation Group C Protein Toll-Like Receptors Imidazoles nutritional and metabolic diseases Cell Polarity Cell Biology medicine.disease 030104 developmental biology Cytokine Cross-Linking Reagents Fanconi Anemia TLR4 Tumor necrosis factor alpha Reactive Oxygen Species DNA Damage |
| Popis: | The Fanconi anemia proteins participate in a canonical pathway that repairs cross-linking agent-induced DNA damage. Cells with inactivated Fanconi anemia genes are universally hypersensitive to such agents. Fanconi anemia-deficient hematopoietic stem cells are also hypersensitive to inflammatory cytokines, and, as importantly, Fanconi anemia macrophages overproduce such cytokines in response to TLR4 and TLR7/8 agonists. We questioned whether TLR-induced DNA damage is the primary cause of aberrantly regulated cytokine production in Fanconi anemia macrophages by quantifying TLR agonist-induced TNF-α production, DNA strand breaks, crosslinker-induced chromosomal breakage, and Fanconi anemia core complex function in Fanconi anemia complementation group C-deficient human and murine macrophages. Although both M1 and M2 polarized Fanconi anemia cells were predictably hypersensitive to mitomycin C, only M1 macrophages overproduced TNF-α in response to TLR-activating signals. DNA damaging agents alone did not induce TNF-α production in the absence of TLR agonists in wild-type or Fanconi anemia macrophages, and mitomycin C did not enhance TLR responses in either normal or Fanconi anemia cells. TLR4 and TLR7/8 activation induced cytokine overproduction in Fanconi anemia macrophages. Also, although TLR4 activation was associated with induced double strand breaks, TLR7/8 activation was not. That DNA strand breaks and chromosome breaks are neither necessary nor sufficient to account for the overproduction of inflammatory cytokines by Fanconi anemia cells suggests that noncanonical anti-inflammatory functions of Fanconi anemia complementation group C contribute to the aberrant macrophage phenotype and suggests that suppression of macrophage/TLR hyperreactivity might prevent cytokine-induced stem cell attrition in Fanconi anemia. |
| Databáze: | OpenAIRE |
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