Abstract

Phagocytes are in constant contact with both living and dying cells. Remarkably, they engulf apoptotic cells with high efficiency while sparing healthy neighbors, a critical distinction maintained by ‘don’t eat-me’ signals. A prominent don’t eat-me signal involves CD47 on live cells engaging SIRPα on phagocytes, recruiting tyrosine phosphatases SHP1/SHP2 to help disengage phagocytes from live cells1,2. Here, we uncover a surprising second function for the SIRP⍺-SHP2 axis: it also tunes the extent of apoptotic cell uptake by phagocytic macrophages and fibroblasts. We first noted phosphorylation of SIRP⍺ and SHP2 in macrophages encountering apoptotic cells in unbiased phosphoproteomics; our subsequent complementary in vitro, in vivo, genetic, and pharmacological approaches revealed that the SIRP⍺-SHP2 axis functions as a ‘don’t eat too much’ brake for apoptotic cell uptake. Macrophages or fibroblasts lacking Sirpα or Shp2 showed enhanced efferocytosis, and conditional Shp2 deletion in mice accelerated wound repair by promoting apoptotic cell removal. Mechanistically, we identified a previously unrecognized transcriptional branch of SIRPα–SHP2-dependent ‘don’t eat too much’ signaling, with unbiased transcriptomics and a CRISPR/Cas9 screen linking the mitochondrial iron importer mitoferrin 2 (SLC25a28) as a key mediator. Together, these findings reveal an unappreciated role for the SIRPα–SHP2 pathway in restraining apoptotic cell uptake, distinct from its canonical role in protecting live cells from phagocytosis.

Committee Chair

Kodi Ravichandran

Committee Members

Marco Colonna, Eynav Klechevsky; John Cooper; Xiaoxiao Wan

Degree

Doctor of Philosophy (PhD)

Author's Department

Biology & Biomedical Sciences (Immunology)

Author's School

Graduate School of Arts and Sciences

Document Type

Dissertation

Date of Award

4-15-2026

Language

English (en)

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Available for download on Sunday, April 09, 2028

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