CLEC-1 promotes early IFN response in cDC1s and favors immune dysregulation during sepsis in mice
TL;DR
It is demonstrated that blocking CLEC-1 using an anti-human CLEC-1 monoclonal antibody mitigates hyperinflammation in CLEC-1 humanized mice and suggests its potential as an immunotherapeutic target.
Abstract
Summary Sepsis is a life-threatening organ dysfunction caused by a dysregulated host immune response, characterized by both hyperinflammation and immunosuppression. Here, we show that the absence of the C-type lectin receptor CLEC-1—expressed particularly by lung cDC1s—improves mouse recovery following E. coli infection. Mechanistically, phenotypic and transcriptomic analyses revealed that Clec1a loss is characterized by an attenuated type I interferon response in lung cDC1s as well as reduced CXCL10 expression and monocyte infiltration during the acute phase of sepsis. Additionally, Clec1a deficiency is associated with an enhanced antigen presentation profile of lung myeloid cells and lower accumulation of regulatory T cells upon secondary infection, suggesting reduced immunoparalysis. Importantly, we demonstrate that blocking CLEC-1 using an anti-human CLEC-1 monoclonal antibody mitigates hyperinflammation in CLEC-1 humanized mice. Together, these findings uncover a role for CLEC-1 in the dysregulation of the inflammatory response during sepsis and suggest its potential as an immunotherapeutic target.