DNGR-1 in dendritic cells limits tissue damage by dampening neutrophil recruitment

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 host-damaging 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, DNGR-1-mediated sensing of injury by cDC1s serves as a rheostat for the control of tissue damage, innate immunity, and immunopathology.C.d.F. is supported by AECC Foundation as recipient of an “Ayuda Fundación Científica AECC a personal investigador en cancer”. P.S.L. is funded by grant BES-2015- 072699 from Spanish Ministerio de Ciencia, Innovación y Universidades (MCIU). M.E. is the recipient of a CNIC International PhD Programme fellowship “la Caixa”-Severo Ochoa OSLCCNIC- 2013-04. S.K.W. is supported by a European Molecular Biology Organization (EMBO) Long-term Fellowship (grant ALTF 438-2016) and a CNIC-International Postdoctoral Programme Fellowship (grant 17230-2016). Work in the D.S. laboratory is funded by the CNIC and grant SAF2016-79040-R from MCIU, Agencia Estatal de Investigación and Fondos Europeos de Desarrollo Regional (FEDER); B2017/BMD-3733 Immunothercan-CM from Comunidad de Madrid; RD16/0015/0018-REEM from FIS-Instituto de Salud Carlos III, MICINN and FEDER; Acteria Foundation; Constantes y Vitales prize (Atresmedia); La Marató de TV3 Foundation (201723); the European Commission (635122-PROCROP H2020) and the European Research Council (ERC-2016-Consolidator Grant 725091). The CNIC is supported by the MCIU and the Pro-CNIC Foundation, and is a Severo Ochoa Center of Excellence (SEV- 2015-0505).S