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

Abstract

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.

A Subset of Type I Conventional Dendritic Cells Controls Cutaneous Bacterial Infections through VEGFα-Mediated Recruitment of Neutrophils

“…It seems likely that similar crosstalk would occur in other skin infections, or even perhaps in other tissue or inflammatory conditions. A recent report demonstrated that during a systemic Candida albicans infection, cDC1 activation regulates neutrophilia via the secretion of the chemokine CXCL2 (Del Fresno et al, 2018). However, we did not detect any Cxcl2 expression in our single-cell cDC1 dataset, but this could be due to the limited detection rate of such technology.…”

Body fluid from the parasitic worm Ascaris suum inhibits broad‐acting pro‐inflammatory programs in dendritic cells

“…7 Based on the transcriptional profile of butyrate-treated LPS + IFN-c-matured DCs, we here find that butyrate treatment of moDC does not lead to an immunosuppressive phenotype as strong as PCF treatment. This is suggested based on the increased butyrate-induced expression of IL18, CXCL8 and IL1B transcript levels, 36,45,46 which are all related to the Type 17 immune axis. Although we identified a strong down-regulation of the IL12B, making it difficult to form the Th17-amplifying cytokine IL-23, other components of a Th17-polarizing phenotype are in play, e.g.…”

“…40 Helminth PCF significantly down-regulated transcripts of IRF8, NFKB1, NFKBIZ, KLF6 and LITAF genes in Type 1 polarizing moDCs, further supporting progression into a non-Th1 and/or Th17 polarizing phenotype. Furthermore, helminth PCF exposure decreased moDC transcript levels for the cytokine-encoding genes IFNB1, IFNL1, LTA, TNF, TNFSF15 and IL1A 33,41-44 and the chemokine-encoding genes CCL3, CCL4, CCL5, CXCL1, CXCL2, CXCL3 and CXCL8, 45,46 which are all associated with promotion of type 1 and/or type 17 immune responses.…”

C-Type Lectin-Like Receptors: Head or Tail in Cell Death Immunity

“…Interestingly, in addition to its role in cross-presentation, CLEC9A exerts also an inhibitory feedback mechanism following tissue damage by activating the negative regulatory signal SHP-1 to dampen neutrophil-mediated immunopathology (132) (Figure 1). In this elegant study, authors showed that the lack of CLEC9A specifically in cDC1 increases the production of MIP-2 and consequently amplifies the recruitment of neutrophils and collateral tissue damage in mouse models of sterile and infectious injury (132). However, the mechanism by which Factin could, according to the context, trigger opposing signals through SYK or SHP-1 remains to be elucidated.…”