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Transcriptional Profiling and Functional Analysis of N1/N2 Neutrophils Reveal an Immunomodulatory Effect of S100A9-Blockade on the Pro-Inflammatory N1 Subpopulation

Mihaila, Andreea C. ; Ciortan, Letitia ; Macarie, Razvan D. ; Vadana, Mihaela ; Cecoltan, Sergiu ; Preda, Mihai Bogdan ; Hudita, Ariana ; Gan, Ana Maria ; Jakobsson, Gabriel LU and Tucureanu, Monica M. , et al. (2021) In Frontiers in Immunology 12.
Abstract

Neutrophils have been classically viewed as a homogenous population. Recently, neutrophils were phenotypically classified into pro-inflammatory N1 and anti-inflammatory N2 sub-populations, but the functional differences between the two subtypes are not completely understood. We aimed to investigate the phenotypic and functional differences between N1 and N2 neutrophils, and to identify the potential contribution of the S100A9 alarmin in neutrophil polarization. We describe distinct transcriptomic profiles and functional differences between N1 and N2 neutrophils. Compared to N2, the N1 neutrophils exhibited: i) higher levels of ROS and oxidative burst, ii) increased activity of MPO and MMP-9, and iii) enhanced chemotactic response. N1... (More)

Neutrophils have been classically viewed as a homogenous population. Recently, neutrophils were phenotypically classified into pro-inflammatory N1 and anti-inflammatory N2 sub-populations, but the functional differences between the two subtypes are not completely understood. We aimed to investigate the phenotypic and functional differences between N1 and N2 neutrophils, and to identify the potential contribution of the S100A9 alarmin in neutrophil polarization. We describe distinct transcriptomic profiles and functional differences between N1 and N2 neutrophils. Compared to N2, the N1 neutrophils exhibited: i) higher levels of ROS and oxidative burst, ii) increased activity of MPO and MMP-9, and iii) enhanced chemotactic response. N1 neutrophils were also characterized by elevated expression of NADPH oxidase subunits, as well as activation of the signaling molecules ERK and the p65 subunit of NF-kB. Moreover, we found that the S100A9 alarmin promotes the chemotactic and enzymatic activity of N1 neutrophils. S100A9 inhibition with a specific small-molecule blocker, reduced CCL2, CCL3 and CCL5 chemokine expression and decreased MPO and MMP-9 activity, by interfering with the NF-kB signaling pathway. Together, these findings reveal that N1 neutrophils are pro-inflammatory effectors of the innate immune response. Pharmacological blockade of S100A9 dampens the function of the pro-inflammatory N1 phenotype, promoting the alarmin as a novel target for therapeutic intervention in inflammatory diseases.

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organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
ABR-238901, N1 neutrophils, N2 neutrophils, neutrophil chemotaxis, neutrophil polarization, RNA-Seq, S100A8/A9
in
Frontiers in Immunology
volume
12
article number
708770
publisher
Frontiers Media S. A.
external identifiers
  • pmid:34447377
  • scopus:85113342021
ISSN
1664-3224
DOI
10.3389/fimmu.2021.708770
language
English
LU publication?
yes
id
7f6a9b5b-0326-44de-8d4a-25887e465e73
date added to LUP
2022-03-21 17:08:16
date last changed
2024-09-11 17:28:19
@article{7f6a9b5b-0326-44de-8d4a-25887e465e73,
  abstract     = {{<p>Neutrophils have been classically viewed as a homogenous population. Recently, neutrophils were phenotypically classified into pro-inflammatory N1 and anti-inflammatory N2 sub-populations, but the functional differences between the two subtypes are not completely understood. We aimed to investigate the phenotypic and functional differences between N1 and N2 neutrophils, and to identify the potential contribution of the S100A9 alarmin in neutrophil polarization. We describe distinct transcriptomic profiles and functional differences between N1 and N2 neutrophils. Compared to N2, the N1 neutrophils exhibited: i) higher levels of ROS and oxidative burst, ii) increased activity of MPO and MMP-9, and iii) enhanced chemotactic response. N1 neutrophils were also characterized by elevated expression of NADPH oxidase subunits, as well as activation of the signaling molecules ERK and the p65 subunit of NF-kB. Moreover, we found that the S100A9 alarmin promotes the chemotactic and enzymatic activity of N1 neutrophils. S100A9 inhibition with a specific small-molecule blocker, reduced CCL2, CCL3 and CCL5 chemokine expression and decreased MPO and MMP-9 activity, by interfering with the NF-kB signaling pathway. Together, these findings reveal that N1 neutrophils are pro-inflammatory effectors of the innate immune response. Pharmacological blockade of S100A9 dampens the function of the pro-inflammatory N1 phenotype, promoting the alarmin as a novel target for therapeutic intervention in inflammatory diseases.</p>}},
  author       = {{Mihaila, Andreea C. and Ciortan, Letitia and Macarie, Razvan D. and Vadana, Mihaela and Cecoltan, Sergiu and Preda, Mihai Bogdan and Hudita, Ariana and Gan, Ana Maria and Jakobsson, Gabriel and Tucureanu, Monica M. and Barbu, Elena and Balanescu, Serban and Simionescu, Maya and Schiopu, Alexandru and Butoi, Elena}},
  issn         = {{1664-3224}},
  keywords     = {{ABR-238901; N1 neutrophils; N2 neutrophils; neutrophil chemotaxis; neutrophil polarization; RNA-Seq; S100A8/A9}},
  language     = {{eng}},
  month        = {{08}},
  publisher    = {{Frontiers Media S. A.}},
  series       = {{Frontiers in Immunology}},
  title        = {{Transcriptional Profiling and Functional Analysis of N1/N2 Neutrophils Reveal an Immunomodulatory Effect of S100A9-Blockade on the Pro-Inflammatory N1 Subpopulation}},
  url          = {{http://dx.doi.org/10.3389/fimmu.2021.708770}},
  doi          = {{10.3389/fimmu.2021.708770}},
  volume       = {{12}},
  year         = {{2021}},
}