Apoptotic Cells Promote Tim4+ Macrophage Differentiation Through Direct and Indirect Signaling Pathways
- 1The Wistar Institute
Abstract
Tissue macrophages are the primary cells responsible for efficiently clearing apoptotic cells, yet how professional efferocyte populations are established remains unclear. Tim4 marks a subset of macrophages across multiple tissues that are highly efferocytic, but the mechanisms governing Tim4 acquisition are poorly understood. Here, we show that monocyte-derived macrophages progressively differentiate into Tim4 macrophages in homeostatic and pathological settings. We identify a cell-autonomous pathway in which efficient apoptotic cell clearance promotes Tim4 acquisition in macrophages, as combined deficiency of CD11b and MerTK impairs both efferocytosis and Tim4 acquisition. Surprisingly, excessive apoptotic cell burden enhanced Tim4 acquisition independently of these receptors. We demonstrate that serial exposure to apoptotic cells induces a type 2 immune response characterized by expansion of IL-4-producing populations and that IL-4R-STAT6 signaling is sufficient and required to drive Tim4 acquisition. These findings support a model in which Tim4 acquisition in macrophages integrates direct signals associated with apoptotic cell clearance and indirect signals generated by apoptotic cell burden. We propose that these complementary mechanisms enable tissues to dynamically adjust the size and function of the professional efferocyte compartment to meet changing demands for apoptotic cell clearance.
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BibTeX
@misc{manning2026apoptotic,
title = {{Apoptotic Cells Promote Tim4+ Macrophage Differentiation Through Direct and Indirect Signaling Pathways}},
author = {B. S. Manning and L. Zhu and B. Murphy and M. M. Soliman and C. Shao and N. Param and T. Miyamoto and R. Shinde and M. Carroll and N. Zhang},
howpublished = {bioRxiv},
year = {2026},
month = oct,
doi = {10.64898/2026.10.12.758552},
url = {https://www.biorxiv.org/content/10.64898/2026.10.12.758552v1},
note = {CC BY-NC-ND},
}
RIS
TY - UNPB
TI - Apoptotic Cells Promote Tim4+ Macrophage Differentiation Through Direct and Indirect Signaling Pathways
AU - B. S. Manning
AU - L. Zhu
AU - B. Murphy
AU - M. M. Soliman
AU - C. Shao
AU - N. Param
AU - T. Miyamoto
AU - R. Shinde
AU - M. Carroll
AU - N. Zhang
PY - 2026
DA - 2026/10/12
PB - bioRxiv
DO - 10.64898/2026.10.12.758552
UR - https://www.biorxiv.org/content/10.64898/2026.10.12.758552v1
AB - Tissue macrophages are the primary cells responsible for efficiently clearing apoptotic cells, yet how professional efferocyte populations are established remains unclear. Tim4 marks a subset of macrophages across multiple tissues that are highly efferocytic, but the mechanisms governing Tim4 acquisition are poorly understood. Here, we show that monocyte-derived macrophages progressively differentiate into Tim4 macrophages in homeostatic and pathological settings. We identify a cell-autonomous pathway in which efficient apoptotic cell clearance promotes Tim4 acquisition in macrophages, as combined deficiency of CD11b and MerTK impairs both efferocytosis and Tim4 acquisition. Surprisingly, excessive apoptotic cell burden enhanced Tim4 acquisition independently of these receptors. We demonstrate that serial exposure to apoptotic cells induces a type 2 immune response characterized by expansion of IL-4-producing populations and that IL-4R-STAT6 signaling is sufficient and required to drive Tim4 acquisition. These findings support a model in which Tim4 acquisition in macrophages integrates direct signals associated with apoptotic cell clearance and indirect signals generated by apoptotic cell burden. We propose that these complementary mechanisms enable tissues to dynamically adjust the size and function of the professional efferocyte compartment to meet changing demands for apoptotic cell clearance.
ER -