Senescent cells suppress macrophage-mediated corpse removal via upregulation of the CD47-QPCT/L axis

Abstract

Progressive accrual of senescent cells in aging and chronic diseases is associated with detrimental effects in tissue homeostasis. We found that senescent fibroblasts and epithelia were not only refractory to macrophage-mediated engulfment and removal, but they also paralyzed the ability of macrophages to remove bystander apoptotic corpses. Senescent cell-mediated efferocytosis suppression (SCES) was independent of the senescence-associated secretory phenotype (SASP) but instead required direct contact between macrophages and senescent cells. SCES involved augmented senescent cell expression of CD47 coinciding with increased CD47-modifying enzymes QPCT/L. SCES was reversible by interfering with the SIRPα-CD47-SHP-1 axis or QPCT/L activity. While CD47 expression increased in human and mouse senescent cells in vitro and in vivo, another ITIM-containing protein, CD24, contributed to SCES specifically in human epithelial senescent cells where it compensated for genetic deficiency in CD47. Thus, CD47 and CD24 link the pathogenic effects of senescent cells to homeostatic macrophage functions, such as efferocytosis, which we hypothesize must occur efficiently to maintain tissue homeostasis.

NLRP3‐Dependent Crosstalk between Pyroptotic Macrophage and Senescent Cell Orchestrates Trauma‐Induced Heterotopic Ossification During Aberrant Wound Healing

“…[ 40 ] Besides, a previous report also suggested that senescent cells could disable the efferocytosis function of macrophages to enable their coexistence within the tissue milieu. [ 41 ] Therefore, we could propose that crosstalk between senescent cells and pyroptotic macrophages might result in positive feedback and thereby led to delayed and persistent inflammation in the injured wound, which caused an aberrant healing response.…”

The YARS Tyrosyl tRNA Synthetase Regulates Senescence Induction and Escape Through the Transcriptional Control of LIN9, a Member of the DREAM Complex

“…YARS down-regulation did not modify p21 level but significantly increased p15 expression in MCF7 cells but not in LS174T cells (Figure 1E and Supplementary Figure 1C, note that p16INK4 is inactivated in the two cell lines). We and others have recently shown that senescent cells can be identified by an increased expression of the CD47 receptor (12,17). Results presented Figure 1F indicate that YARS inhibition led to a significant increase in the number of CD47 high MCF7 cells.…”

Caveolin scaffolding domain (CSD) peptide LTI-2355 modulates the phagocytic and synthetic activity of lung derived myeloid cells in Idiopathic Pulmonary Fibrosis (IPF) and Post-acute sequelae of COVID-fibrosis (PASC-F)

“…However, in the present study we examined the overall adherent lung myeloid population isolated from human lung explants without distinguishing between satiated (i.e., CD11b low phenotype) or activated (i.e., CD11b high phenotype). Schloesser D et al (Schloesser et al, 2023) showed that a suppressed macrophage phenotype was mediated through a cell contact-dependent interaction with senescent fibroblasts. While our results indicate that primary IPF and PASC fibrosis myeloid cells showed an intrinsic suppression of myeloid cell activity, future studies will address the role of the senescent environment on the impairment of IPF and PASC-F lung myeloid cells and whether LTI-2355 alters the functionality of these myeloid cells such that these cells exhibit a pro-resolving phenotype (Zhang et al, 2020).…”