期刊
SCIENCE
卷 362, 期 6412, 页码 351-+出版社
AMER ASSOC ADVANCEMENT SCIENCE
DOI: 10.1126/science.aan8423
关键词
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资金
- AECC Foundation
- Spanish Ministerio de Ciencia, Innovacion y Universidades (MCIU) [BES-2015-072699]
- CNIC International Ph.D. Programme fellowship la Caixa-Severo Ochoa [OSLC-CNIC-2013-04]
- European Molecular Biology Organization (EMBO) Long-Term Fellowship [ALTF 438-2016]
- CNIC-International Postdoctoral Programme Fellowship [17230-2016]
- CNIC
- MCIU [SAF2016-79040-R]
- Agencia Estatal de Investigacion
- Fondos Europeos de Desarrollo Regional (FEDER)
- Immunothercan-CM from Comunidad de Madrid [B2017/BMD-3733]
- FIS-Instituto de Salud Carlos III [RD16/0015/0018-REEM]
- MICINN
- FEDER
- Acteria Foundation
- Constantes y Vitales prize (Atresmedia)
- La Marato de TV3 Foundation [201723]
- European Commission [635122-PROCROP H2020]
- European Research Council (ERC-2016-Consolidator Grant) [725091]
- MCIU
- Pro-CNIC Foundation
- Severo Ochoa Center of Excellence [SEV-2015-0505]
Host injury triggers feedback mechanisms that limit tissue damage. Conventional type 1 dendritic cells (cDC1s) express dendritic cell natural killer lectin group receptor-1 (DNGR-1), encoded by the gene Clec9a, which senses tissue damage and favors cross-presentation of dead-cell material to CD8(+) T cells. Here we find that DNGR-1 additionally reduces hostdamaging inflammatory responses induced by sterile and infectious tissue injury in mice. DNGR-1 deficiency leads to exacerbated caerulein-induced necrotizing pancreatitis and increased pathology during systemic Candida albicans infection without affecting fungal burden. This effect is B and T cell-independent and attributable to increased neutrophilia in DNGR-1-deficient settings. Mechanistically, DNGR-1 engagement activates SHP-1 and inhibits MIP-2 (encoded by Cxcl2) production by cDC1s during Candida infection. This consequently restrains neutrophil recruitment and promotes disease tolerance. Thus, DNGR1-mediated sensing of injury by cDC1s serves as a rheostat for the control of tissue damage, innate immunity, and immunopathology.
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