Cited by 82Phagocytosis and Immune RegulationAtherosclerosis and Cardiovascular DiseasesImmune cells in cancer

Efferocytosis drives a tryptophan metabolism pathway in macrophages to promote tissue resolution

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Sukka, Santosh R., Ampomah, Patrick B., Darville, Lancia N. F., Ngai, David, Wang, Xiaobo, Kuriakose, George, Xiao, Yuling, Shi, Jinjun +3 more·2024·Nature Metabolism

Abstract

Macrophage efferocytosis prevents apoptotic cell (AC) accumulation and triggers inflammation-resolution pathways. The mechanisms linking efferocytosis to resolution often involve changes in macrophage metabolism, but many gaps remain in our understanding of these processes. We now report that efferocytosis triggers an indoleamine 2,3-dioxygenase-1 (IDO1)-dependent tryptophan (Trp) metabolism pathway that promotes several key resolution processes, including the induction of pro-resolving proteins, such interleukin-10, and further enhancement of efferocytosis. The process begins with upregulation of Trp transport and metabolism, and it involves subsequent activation of the aryl hydrocarbon receptor (AhR) by the Trp metabolite kynurenine (Kyn). Through these mechanisms, macrophage IDO1 and AhR contribute to a proper resolution response in several different mouse models of efferocytosis-dependent tissue repair, notably during atherosclerosis regression induced by plasma low-density lipoprotein (LDL) lowering. These findings reveal an integrated metabolism programme in macrophages that links efferocytosis to resolution, with possible therapeutic implications for non-resolving chronic inflammatory diseases, notably atherosclerosis.

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  • Efferocytosis leads to IL-10 induction in macrophages through signaling pathways activated by apoptotic cell cargo, including fatty acids and tryptophan.

    “Efferocytosis leads to IL-10 induction in macrophages through signaling pathways activated by apoptotic cell cargo, including fatty acids and tryptophan (30, 40).”

    From Impaired TIM4-mediated efferocytosis by liver macrophages contributes to fibrosis in metabolic dysfunction–associated steatohepatitis (2025) · cites this paper as [30]

    The Results section ('IDO1 licences post-efferocytic resolution in macrophages'; page not specified) reports that efferocytosis increases macrophage IL-10 and that this increase depends in part on the tryptophan-metabolism pathway. The Extended Data describe apoptotic-cell-derived tryptophan leading to Il10 transcription through kynurenine and AhR. Our copy does not establish the claimed fatty-acid-cargo pathway to IL-10 induction. (LLM, conf=0.87)

    Experimental — accuracy not yet measured
  • IL-10 is among the proresolving molecules known to be induced by efferocytosis.

    “Among the proresolving molecules known to be induced by efferocytosis is interleukin-10 (IL-10) (30, 40)”

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Authors
Sukka, S. R., Ampomah, P. B., Darville, L. N. F., Ngai, D., Wang, X., Kuriakose, G., Xiao, Y., Shi, J., Koomen, J. M., McCusker, R. H., & Tabas, I.
Affiliations
  • Columbia University Irving Medical Center (US)
  • Moffitt Cancer Center (US)
  • Brigham and Women's Hospital (US)
  • University of Illinois Urbana-Champaign (US)
Corresponding author
  • Sukka, Santosh R.
  • Tabas, Ira
Venue
Nature Metabolism
Published
2024-09-06
Volume
6
Issue
9
Pages
1736-1755
ISSN
2522-5812 (ISSN-L)
OpenAlex
W4402316299
Cited by
82
References
80
Citations by year
2026: 45 · 2025: 35 · 2024: 2
FWCI
13.60
Type
journal article
Language
en
Open access
Locations
  • Nature Metabolism (publishedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
  • Digital Access to Scholarship at Harvard (DASH) (Harvard University) (submittedVersion, cc-by)
Funders
  • U.S. Department of Health & Human Services | NIH | National Heart, Lung, and Blood Institute (HL145228, HL087123, HL159012)
  • U.S. Department of Health & Human Services | NIH | National Cancer Institute (P30 CA076292)
Topics
  • Life Sciences › Immunology and Microbiology › Immunology › Phagocytosis and Immune Regulation
  • Life Sciences › Immunology and Microbiology › Immunology › Atherosclerosis and Cardiovascular Diseases
  • Life Sciences › Immunology and Microbiology › Immunology › Immune cells in cancer
Keywords
efferocytosis, macrophages, tryptophan metabolism, IDO1, aryl hydrocarbon receptor, kynurenine, inflammation resolution, IL-10, atherosclerosis regression, chronic inflammation, macrophage metabolism
MeSH terms
Efferocytosis, Animals, Inflammation, Kynurenine, Macrophages, Phagocytosis, Tryptophan, Apoptosis, Receptors, Aryl Hydrocarbon, Atherosclerosis, Indoleamine-Pyrrole 2,3,-Dioxygenase, Mice

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