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

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Science  19 Oct 2018:
Vol. 362, Issue 6412, pp. 351-356
DOI: 10.1126/science.aan8423

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The absence of DNGR-1 is dangerous

Conventional type 1 dendritic cells (cDC1s) can sense tissue damage via DNGR-1, which binds F-actin exposed by necrotic cells. DNGR-1 activation favors cross-presentation, the process by which extracellular antigens are processed and presented to CD8+ T cells via major histocompatibility complex class I molecules. Del Fresno et al. studied mice lacking DNGR-1 and found that DNGR-1 also has anti-inflammatory effects (see the Perspective by Salazar and Brown). It inhibits the secretion of the chemokine CXCL2 by cDC1s, which, in turn, limits neutrophil recruitment. Thus, DNGR-1 connects cell-death sensing with a mechanism of damage control.

Science, this issue p. 351; see also p. 292


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.

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