2. Academic Validation
  3. PP4 modulates macrophage-neutrophil crosstalk to restrict CCL5 -driven NETosis in sepsis

PP4 modulates macrophage-neutrophil crosstalk to restrict CCL5 -driven NETosis in sepsis

  • Redox Biol. 2026 Apr:91:104093. doi: 10.1016/j.redox.2026.104093.
Feng-Ming Yang 1,  Shih-Chang Hsu 2,  Yu-Chih Wu 3,  Ching-Lu Chen 4,  Tse-Hua Tan 5,  Szu-Yi Chou 6,  Hui-Ming Chang 7,  Edward T H Yeh 8
Affiliations

Affiliations

  • 1 Graduate Institute of Physiology, National Taiwan University College of Medicine, Taipei, Taiwan. Electronic address: [email protected].
  • 2 Department of Emergency, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan; Emergency Department, Wan Fang Hospital, Taipei Medical University, Taipei, Taiwan; Graduate Institute of Medical Sciences, College of Medicine, Taipei Medical University, Taipei, Taiwan.
  • 3 School of Respiratory Therapy, College of Medicine, Taipei Medical University, Taipei, Taiwan.
  • 4 Emergency Department, Wan Fang Hospital, Taipei Medical University, Taipei, Taiwan; Graduate Institute of Medical Sciences, College of Medicine, Taipei Medical University, Taipei, Taiwan.
  • 5 Immunology Research Center, National Health Research Institutes, Zhunan, Taiwan.
  • 6 Ph.D. Program in Medical Neuroscience, College of Medical Science and Technology, Taipei Medical University and National Health Research Institute, Taipei, Taiwan; Graduate Institute of Neural Regenerative Medicine, College of Medical Science and Technology, Taipei, Taiwan.
  • 7 Department of Pharmacology and Toxicology, University of Arkansas for Medical Sciences, Little Rock, AR, USA; Department of Internal Medicine, University of Arkansas for Medical Sciences, Little Rock, AR, USA; Winthrop P. Rockefeller Cancer Institute, University of Arkansas for Medical Sciences, Little Rock, AR, USA.
  • 8 Department of Internal Medicine, University of Arkansas for Medical Sciences, Little Rock, AR, USA; Winthrop P. Rockefeller Cancer Institute, University of Arkansas for Medical Sciences, Little Rock, AR, USA.
PMID: 41723906 DOI: 10.1016/j.redox.2026.104093
Abstract

Sepsis is a life-threatening clinical syndrome caused by a dysregulated innate immune response to Infection, resulting in excessive systemic inflammation, multi-organ failure, and persistently high mortality rates. In fatal human sepsis, PP4 expression is markedly reduced in myeloid cells, suggesting a protective role against dysregulated innate immunity. However, its role in macrophage-neutrophil crosstalk during sepsis environment remains unclear. To delineate its cell-type specificity, we generated myeloid cell-specific PP4 knockout mice and investigated PP4's function in innate immune regulation during sepsis. PP4-deficient mice exhibited significantly increased susceptibility to sepsis, with severe tissue damage following cecal ligation and puncture (CLP) or endotoxin challenge. Mechanistically, PP4 modulates macrophage-neutrophil crosstalk during the sepsis environment, with its loss leading to dysregulated CCL5/CCR5 signaling, driving excessive neutrophil activation. Elevated macrophage-derived CCL5 enhanced PAD4-dependent NETosis, ROS production, and Elastase activity via CCR5, while CCR5 inhibition effectively mitigated neutrophil hyperactivity. At the molecular level, PP4 directly dephosphorylated TBK1, thereby inactivating IRF3 and suppressing macrophage-driven CCL5 production. Furthermore, ERK1/2 phosphorylation upregulated CCR5 expression in PP4-deficient neutrophils post-CLP, amplifying the CCL5/CCR5-mediated NETosis response. Notably, transfection with wild-type PP4-but not a phosphatase-deficient mutant-reduced LPS-mediated CCR5 expression in neutrophils, thereby limiting ROS production and NETs formation. These findings establish PP4 as a critical regulator of CCL5/CCR5-driven NETosis, uncovering a novel therapeutic target for modulating innate immune responses in sepsis.

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