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Cited by 61Immune cells in cancerWound Healing and TreatmentsPhagocytosis and Immune Regulation

Inflammatory M1-like macrophages polarized by NK-4 undergo enhanced phenotypic switching to an anti-inflammatory M2-like phenotype upon co-culture with apoptotic cells

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Kohno, Keizo, Koya-Miyata, Satomi, Harashima, Akira, Tsukuda, Takahiko, Katakami, Masataka, Ariyasu, Toshio, Ushio, Shimpei, Iwaki, Kanso·2021·Journal of Inflammation
DOI 10.1186/s12950-020-00267-zPMC PMC7791770

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Abstract

Background: NK-4 has been used to promote wound healing since the early-1950s; however, the mechanism of action of NK-4 is unknown. In this study, we examined whether NK-4 exerts a regulatory effect on macrophages, which play multiple roles during wound healing from the initial inflammatory phase until the tissue regeneration phase. Results: NK-4 treatment of THP-1 macrophages induced morphological features characteristic of classically-activated M1 macrophages, an inflammatory cytokine profile, and increased expression of the M1 macrophage-associated molecules CD38 and CD86. Interestingly, NK-4 augmented TNF-α production by THP-1 macrophages in combination with LPS, Pam3CSK4, or poly(I:C). Furthermore, NK-4 treatment enhanced THP-1 macrophage phagocytosis of latex beads. These results indicate that NK-4 drives macrophage polarization toward an inflammatory M1-like phenotype with increased phagocytic activity. Efferocytosis is a crucial event for resolution of the inflammatory phase in wound healing. NK-4-treated THP-1 macrophages co-cultured with apoptotic Jurkat E6.1 (Apo-J) cells switched from an M1-like phenotype to an M2-like phenotype, as seen in the inverted ratio of TNF-α to IL-10 produced in response to LPS. We identified two separate mechanisms that are involved in this phenotypic switch. First, recognition of phosphatidylserine molecules on Apo-J cells by THP-1 macrophages downregulates TNF-α production. Second, phagocytosis of Apo-J cells by THP-1 macrophages and activation of PI3K/Akt signaling pathway upregulates IL-10 production. Conclusion: It is postulated that the phenotypic switch from a proinflammatory M1-like phenotype to an anti-inflammatory M2-like phenotype is dysregulated due to impaired efferocytosis of apoptotic neutrophils at the wound site. Our results demonstrate that NK-4 improves phagocytosis of apoptotic cells, suggesting its potential as a therapeutic strategy to resolve sustained inflammation in chronic wounds.

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  • Transition from the M1 to M2 phenotype is essential to resolve inflammation.

    “Transition from the M1 to M2 phenotype is essential to resolve inflammation [188].”

    From MicroRNAs as Regulators of Phagocytosis (2022) · cites this paper as [188]

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Cited by

Sorted by citations

Authors
Kohno, K., Koya-Miyata, S., Harashima, A., Tsukuda, T., Katakami, M., Ariyasu, T., Ushio, S., & Iwaki, K.
Affiliations
Hayashibara (Japan) (JP)
Corresponding author
Kohno, Keizo
ORCID
Kohno, Keizo
Venue
Journal of Inflammation
Publisher
Springer Science and Business Media LLC
Published
2021-01-07
Volume
18
Issue
1
Pages
2-2
ISSN
1476-9255 (ISSN-L)
DOI
10.1186/s12950-020-00267-z
PMC
PMC7791770
OpenAlex
W3120917195
Cited by
61
References
2
Citations by year
2026: 6 · 2025: 14 · 2024: 9 · 2023: 10 · 2022: 16 · 2021: 6
FWCI
3.82
Type
journal article
Language
en
Open access
Licence
Locations
  • Journal of Inflammation (publishedVersion, cc-by)
  • Research Square (acceptedVersion, cc-by)
  • Europe PMC (PubMed Central) (publishedVersion, other-oa)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
Hayashibara Co., Ltd.
Topics
  • Life Sciences › Immunology and Microbiology › Immunology › Immune cells in cancer
  • Health Sciences › Medicine › Rehabilitation › Wound Healing and Treatments
  • Life Sciences › Immunology and Microbiology › Immunology › Phagocytosis and Immune Regulation
Keywords
macrophage polarization, M1 macrophages, M2 macrophages, efferocytosis, apoptotic cells, wound healing, chronic wounds, phagocytosis, phosphatidylserine, TNF-α, IL-10, PI3K/Akt signaling, CD38, CD86, THP-1 macrophages, neutrophil apoptosis

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