{
  "abstract": "Complement protein C3 is crucial for immune responses in mucosal sites such as the lung, where it aids in microbe elimination and enhances inflammation. While trained immunity – enhanced secondary responses of innate immune cells after prior exposure – is well-studied, the role of the complement system in trained immune responses remains unclear. We investigated the role of C3 in trained immunity and found that alveolar macrophage C3 and C3aR1 expression increased in humans after an intranasal exposure to a training stimulus. In vivo , trained wild-type mice showed significantly elevated pro-inflammatory cytokines and increased C3a levels upon a second stimulus. Ex vivo , trained C3-deficient alveolar macrophages (AMs) displayed reduced chemokine and cytokine output as well as impaired phagocytosis and reactive oxygen species (ROS) production compared to wildtype AMs. Real-time confocal microscopy of live, intact mouse alveoli revealed that AMs internalize C3 rapidly after alveolar microinstillation, as compared to C3a. Correspondingly, the blunted cytokine output was restored by exogenous C3 but not by C3a. Inhibiting C3aR, both pharmacologically and with a genetic C3aR knockout, prevented this restoration, indicating the necessity of C3aR engagement. Mechanistically, trained WT AMs demonstrated enhanced glycolytic activity compared to C3-deficient AMs – a defect corrected by exogenous C3 in a C3aR-dependent manner. These findings reveal that C3 modulates trained immunity in AMs through C3aR signaling and highlight a novel role for C3 in trained immunity.",
  "abstract_shown": true,
  "affiliations": [
    "Divisions of Pulmonary and Critical Care Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA",
    "Washington University School of Medicine",
    "Departments of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA",
    "University of California-Los Angeles",
    "Lung Imaging Laboratory, Division of Pulmonary, Critical Care, and Sleep Medicine, Department of Medicine, Icahn School of Medicine at Mount Sinai, Icahn School of Medicine at Mount Sinai, New York, NY, USA",
    "Divisions of Rheumatology, John T. Milliken Department of Medicine, Washington University School of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA",
    "Departments of Anesthesia, University of California, Los Angeles David Geffen School of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA",
    "Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY, USA",
    "Department of Stem Cell Biology and Regenerative Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA"
  ],
  "article_type": null,
  "arxiv": null,
  "author_total": 18,
  "authors": [
    {
      "affs": [
        0,
        1
      ],
      "name": "Alexander Earhart",
      "orcid": "0000-0002-8015-6026"
    },
    {
      "affs": [
        2,
        1
      ],
      "name": "Alberto Lopez",
      "orcid": "0000-0002-6218-5587"
    },
    {
      "affs": [
        2,
        1
      ],
      "name": "Josue I. Hernandez",
      "orcid": "0009-0007-2437-2457"
    },
    {
      "affs": [
        2,
        3
      ],
      "name": "Aasritha Nallapu",
      "orcid": "0009-0000-1189-8547"
    },
    {
      "affs": [
        4,
        1
      ],
      "name": "Deebly Chavez"
    },
    {
      "affs": [
        4,
        1
      ],
      "name": "Sayahi Suthakaran"
    },
    {
      "affs": [
        2,
        1
      ],
      "name": "Brian Yang",
      "orcid": "0009-0002-4902-3628"
    },
    {
      "affs": [
        2,
        1
      ],
      "name": "Jungheun Hyun",
      "orcid": "0000-0001-6927-6177"
    },
    {
      "affs": [
        0,
        1
      ],
      "name": "Rafael Aponte Alburquerque",
      "orcid": "0000-0002-4771-2801"
    },
    {
      "affs": [
        0,
        3
      ],
      "name": "Marick Starick",
      "orcid": "0000-0003-4227-7852"
    },
    {
      "affs": [
        0
      ],
      "name": "Lorena Garnica",
      "orcid": "0009-0003-7644-6535"
    },
    {
      "affs": [
        0
      ],
      "name": "Ayşe Naz Ozantürk",
      "orcid": "0000-0002-0187-3642"
    },
    {
      "affs": [
        0
      ],
      "name": "Rahul Kumar Maurya",
      "orcid": "0009-0007-6996-5459"
    },
    {
      "affs": [
        5
      ],
      "name": "Xiaobo Wu",
      "orcid": "0000-0002-6703-2272"
    },
    {
      "affs": [
        0
      ],
      "name": "Jeffrey A. Haspel",
      "orcid": "0000-0001-5839-0265"
    },
    {
      "affs": [
        6
      ],
      "name": "Jae Woo Lee"
    },
    {
      "affs": [
        7,
        8,
        4
      ],
      "name": "Jaime L. Hook",
      "orcid": "0000-0002-6630-0060"
    },
    {
      "affs": [
        2,
        0
      ],
      "name": "Hrishikesh S. Kulkarni",
      "orcid": "0000-0003-4830-5084"
    }
  ],
  "bibtex": "https://research.draconitic.com/paper/7b7dcdbgs7gy5.bib",
  "cited_by": 5,
  "doi": "10.7554/elife.104977.3",
  "fulltext_url": null,
  "id": "7b7dcdbgs7gy5",
  "issns": [
    "2050-084X"
  ],
  "landing_url": "https://doi.org/10.7554/elife.104977.3",
  "language": "en",
  "licence": "CC-BY",
  "licence_label": "CC BY",
  "licence_source": "journal",
  "licence_url": "https://creativecommons.org/licenses/by/4.0/",
  "metadata_licence": null,
  "native_subjects": [
    [
      "openalex",
      "2403|Immune responses and vaccinations"
    ]
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  "openalex": "W4404018477",
  "pdf_url": null,
  "pmcid": "PMC11565986",
  "pmid": "39554000",
  "published": "2026-08-18",
  "publisher": "eLife Sciences Publications Ltd",
  "ris": "https://research.draconitic.com/paper/7b7dcdbgs7gy5.ris",
  "sources": [
    {
      "first_seen": "2026-11-04T13:21:10Z",
      "native_id": "W4404018477",
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      "url": "https://doi.org/10.7554/elife.104977.3"
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  "subjects": [
    {
      "field": "biology",
      "origin": "openalex:2403|Immune responses and vaccinations",
      "subfield": "immunology"
    }
  ],
  "title": "The C3–C3aR axis modulates trained immunity in alveolar macrophages",
  "title_text": "The C3–C3aR axis modulates trained immunity in alveolar macrophages",
  "type": "peer-reviewed",
  "updated_at": "2026-11-06T13:20:33Z",
  "url": "https://research.draconitic.com/paper/7b7dcdbgs7gy5",
  "venue": "eLife",
  "versions": []
}