CLEC-1 Restrains Acute Inflammatory Response and Recruitment of Neutrophils following Tissue Injury.

The inflammatory response is a key mechanism for the elimination of injurious agents but must be tightly controlled to prevent additional tissue damage and progression to persistent inflammation. C-type lectin receptors expressed mostly by myeloid cells play a crucial role in the regulation of inflammation by recognizing molecular patterns released by injured tissues. We recently showed that the C-type lectin receptor CLEC-1 is able to recognize necrotic cells. However, its role in the acute inflammatory response following tissue damage had not yet been investigated. We show in this study, in a mouse model of liver injury induced by acetaminophen intoxication, that Clec1a deficiency enhances the acute immune response with increased expression of Il1b, Tnfa, and Cxcl2 and higher infiltration of activated neutrophils into the injured organ. Furthermore, we demonstrate that Clec1a deficiency exacerbates tissue damage via CXCL2-dependent neutrophil infiltration. In contrast, we observed that the lack of CLEC-1 limits CCL2 expression and the accumulation, beyond the peak of injury, of monocyte-derived macrophages. Mechanistically, we found that Clec1a-deficient dendritic cells increase the expression of Il1b, Tnfa, and Cxcl2 in response to necrotic cells, but decrease the expression of Ccl2. Interestingly, treatment with an anti-human CLEC-1 antagonist mAb recapitulates the exacerbation of acute immunopathology observed by genetic loss of Clec1a in a preclinical humanized mouse model. To conclude, our results demonstrate that CLEC-1 is a death receptor limiting the acute inflammatory response following injury and represents a therapeutic target to modulate immunity.

CLEC-1 is a death sensor that limits antigen cross-presentation by dendritic cells and represents a target for cancer immunotherapy.

Tumors exploit numerous immune checkpoints, including those deployed by myeloid cells to curtail antitumor immunity. Here, we show that the C-type lectin receptor CLEC-1 expressed by myeloid cells senses dead cells killed by programmed necrosis. Moreover, we identified Tripartite Motif Containing 21 (TRIM21) as an endogenous ligand overexpressed in various cancers. We observed that the combination of CLEC-1 blockade with chemotherapy prolonged mouse survival in tumor models. Loss of CLEC-1 reduced the accumulation of immunosuppressive myeloid cells in tumors and invigorated the activation state of dendritic cells (DCs), thereby increasing T cell responses. Mechanistically, we found that the absence of CLEC-1 increased the cross-presentation of dead cell-associated antigens by conventional type-1 DCs. We identified antihuman CLEC-1 antagonist antibodies able to enhance antitumor immunity in CLEC-1 humanized mice. Together, our results demonstrate that CLEC-1 acts as an immune checkpoint in myeloid cells and support CLEC-1 as a novel target for cancer immunotherapy.