Leader: Silvano Sozzani (SAPIENZA); Other collaborator(s):
The accumulation of senescent cells in tissues underlies age-related disorders. Our initial effort concentrated on a reversible form of senescence endowed with an inflammatory secretome capable of recruiting and activating neutrophils, in part through the action of interleukin-8 (IL-8) and acute-phase serum amyloid A1 (SAA1). These findings may be relevant for the control of tissue local inflammation. As a second aspect of the project that was pursued, we characterized the regulation of chemotactic receptors in senescent neutrophils. Senescent cells upregulated CXCR4 and CCRL2. By FRET analysis we found that CCRL2 regulates CXCR4 signalling by the formation of heterodimers.
Brief description of the activities and of the intermediate results:The accumulation of senescent cells in tissues is a key driver of age-related disorders. Senescent cells profoundly influence the surrounding microenvironment by secreting numerous bioactive molecules and inflammatory factors. In this study, we investigated the induction of cellular senescence within the inflammatory tumor microenvironment using breast cancer cells, with a specific focus on senescent neutrophils. We identified a reversible form of tumor cell senescence that exhibits an inflammatory secretome capable of recruiting and activating neutrophils, partially mediated by CXCL8 and acute-phase serum amyloid A1. Neutrophil activation was associated with the release of neutrophil extracellular traps (NETs) and the phagocytic clearance of senescent tumor cells. Our findings revealed that, similar to macrophages and natural killer cells, neutrophils can be recruited and engaged by senescent tumor cells to facilitate their removal.
Furthermore, single-cell RNA sequencing (scRNA-seq) identified a unique phenotype of tumor-infiltrating senescent neutrophils, characterized by reprogrammed expression of chemotactic receptors. Specifically, senescent cells upregulated CXCR4 and CCRL2. Using FRET analysis, we demonstrated that CCRL2 forms heterodimers with CXCR4. Biochemical and functional assays suggest that CCRL2 expression may regulate CXCR4 functions through this mechanism.
Finally, we are currently investigating the interaction between CCRL2 and CMKLR1, a functional chemotactic receptor that shares the ligand chemerin with CCRL2.
Brief description of the activities and of the intermediate results:The accumulation of senescent cells in tissues is a key driver of age-related disorders. Senescent cells profoundly influence the surrounding microenvironment by secreting numerous bioactive molecules and inflammatory factors. In this study, we investigated the induction of cellular senescence within the inflammatory tumor microenvironment using breast cancer cells, with a specific focus on senescent neutrophils. We identified a reversible form of tumor cell senescence that exhibits an inflammatory secretome capable of recruiting and activating neutrophils, partially mediated by CXCL8 and acute-phase serum amyloid A1. Neutrophil activation was associated with the release of neutrophil extracellular traps (NETs) and the phagocytic clearance of senescent tumor cells. Our findings revealed that, similar to macrophages and natural killer cells, neutrophils can be recruited and engaged by senescent tumor cells to facilitate their removal.
Furthermore, single-cell RNA sequencing (scRNA-seq) identified a unique phenotype of tumor-infiltrating senescent neutrophils, characterized by reprogrammed expression of chemotactic receptors. Specifically, senescent cells upregulated CXCR4 and CCRL2. Using FRET analysis, we demonstrated that CCRL2 forms heterodimers with CXCR4. Biochemical and functional assays suggest that CCRL2 expression may regulate CXCR4 functions through this mechanism.
Experiments on the interaction between CCRL2 and CMKLR1, a functional chemotactic receptor that shares the ligand chemerin with CCRL2, are ongoing.
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