Molecular control of PDPNhi macrophage subset induction by ADAP as a host defense in sepsis
Open accessAbstract
Induction of podoplanin (PDPN) expression is a critical response of macrophages to LPS stimulation or bacterial infection in sepsis, but how this key process of TLR4-stimulated PDPN upregulation is regulated and the effect of PDPN expression on macrophage function remain elusive. Here, we determined how this process is regulated in vitro and in vivo. PDPN failed to be upregulated in TLR4-stimulated macrophages deficient in adhesion and degranulation-promoting adapter protein (ADAP), which could be rescued by the reconstitution of ADAP. A distinct PDPN hi peritoneal macrophage (PM) subset, which exhibited an M2-like phenotype and enhanced phagocytic activity, was generated in WT but not in ADAP-deficient septic mice. The blockade of PDPN hi PMs mimicked the effect of ADAP deficiency, which exacerbated sepsis. Mechanistically, Bruton’s tyrosine kinase–mediated (BTK-mediated) tyrosine phosphorylation of ADAP at Y 571 worked together with mTOR to converge on STAT3 activation for the transactivation of the PDPN promoter. Moreover, agonist activation of STAT3 profoundly potentiated the PDPN hi PM subset generation and alleviated sepsis severity in mice. Together, our findings reveal a mechanism whereby ADAP resets macrophage function by controlling the TLR4-induced upregulation of PDPN as a host innate immune defense during sepsis.
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In sepsis, ADAP alleviates systemic inflammation by reshaping macrophage function through TLR4-induced PDPN expression.
“In sepsis, ADAP alleviates systemic inflammation by reshaping macrophage function through TLR4-induced PDPN expression [19].”
From Inhibition of SPI1 by ADAP Regulates S100A8/A9 Signaling in Macrophages to Control the Development of Colitis (2026) · cites this paper as [19]
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- Authors
- Zhang, P., Wang, X., Yang, X., & Liu, H.
- Affiliations
- Soochow University (CN)
- Second Affiliated Hospital of Soochow University (CN)
- Corresponding author
- Liu, Hebin
- Venue
- JCI Insight
- Published
- 2025-02-04
- Volume
- 10
- Issue
- 6
- ISSN
- 2379-3708 (ISSN-L)
- PMC
- PMC11949065
- OpenAlex
- W4407133453
- Cited by
- 10
- References
- 49
- Citations by year
- 2026: 8 · 2025: 2
- FWCI
- 3.70
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- JCI Insight (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- Natural Science Foundation of Jiangsu Higher Education Institution-Key Program (21KJA310002)
- Soochow University Research Development Funds (Q424900220)
- Soochow University Interdisciplinary Medicine Program Funds (50340000122)
- Suzhou Key Program Special Funds in XJTLU (KSF-A-21)
- National Natural Science Foundation of China (31470840)
- Topics
- Life Sciences › Immunology and Microbiology › Immunology › Immune Response and Inflammation
- Health Sciences › Medicine › Epidemiology › Sepsis Diagnosis and Treatment
- Life Sciences › Immunology and Microbiology › Immunology › Inflammation biomarkers and pathways
- Keywords
- podoplanin, ADAP, sepsis, macrophage polarization, M2 macrophages, TLR4 signaling, Bruton's tyrosine kinase, STAT3 activation, mTOR, peritoneal macrophages, innate immunity, host defense, phagocytosis, LPS
- MeSH terms
- Agammaglobulinaemia Tyrosine Kinase, Animals, Disease Models, Animal, Lipopolysaccharides, Macrophages, Male, Membrane Glycoproteins, Mice, Inbred C57BL, Phosphorylation, Signal Transduction, Macrophages, Peritoneal, Mice, Knockout, Sepsis, Adaptor Proteins, Signal Transducing, STAT3 Transcription Factor, Toll-Like Receptor 4, Mice, TOR Serine-Threonine Kinases
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