# Dual neutrophil subsets accelerate or brake inflammation in tuberculosis

Emilie Doz-Deblauwe, Badreddine Bounab, Florence Carreras, Julia Siveira Fahel, Sergio Oliveira, Mohamed Lamkanfi, Yves Le Vern, Pierre Germon, Julien Pichon, Christophe Paget, et al.

► To cite this version:

Emilie Doz-Deblauwe, Badreddine Bounab, Florence Carreras, Julia Siveira Fahel, Sergio Oliveira, et al. Dual neutrophil subsets accelerate or brake inflammation in tuberculosis. Neutrophil 2024, Sep 2024, Munich, Germany. . [hal-04717343](https://hal.inrae.fr/hal-04717343v1)

HAL Id: hal-04717343

https://hal.inrae.fr/hal-04717343v1

Submitted on 1 Oct 2024

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Distributed under a Creative Commons Attribution 4.0 International License
# Dual neutrophil subsets accelerate or brake inflammation in tuberculosis.

Emilie DOZ DEBLAUWE¹, Badreddine BOUNAB¹, Florence CARRERAS¹, Julia SIVEIRA FAHEL³, Sergio OLIVEIRA⁴, Mohamed LAMKANFI⁵, Yves LEVERN¹, Pierre GERMON¹, Julien PICHON¹, Christophe PAGET², Aude REMOT¹ and Nathalie WINTER¹

¹ INRAE, University of Tours UMR ISP 1282, France ; ² INSERM, University of Tours CEPR, ³ Federal University of Minas Gerais, Belo Horizonte, Brazil, ⁴ University of Sao Paolo, Brazil, ⁵ Ghent University, Belgium

Neutrophils can be beneficial or deleterious during tuberculosis (TB). Based on the expression of MHC-II and programmed death ligand 1 (PD-L1), we distinguished two functionally and transcriptionally distinct neutrophil subsets in the lungs of mice infected with mycobacteria. Inflammatory [MHC-II-, PD-L1⁹] neutrophils produced inflammasome-dependent IL-1β in the lungs in response to virulent mycobacteria and “accelerated” deleterious inflammation, which was highly exacerbated in IFN-γR-/- mice. Regulatory [MHC-II+, PD-L1hi] neutrophils “brake” inflammation by suppressing T-cell proliferation and IFN-γ production. Such beneficial regulation, which depends on PD-L1, is controlled by IFN-γR signaling in neutrophils. These findings add a layer of complexity to the roles played by neutrophils in TB and may explain the reactivation of this disease observed in cancer patients treated with anti-PD-L1.

## 1- Two neutrophil subsets with two different functions

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MHC-II<sup>neg</sup> neutrophils produce IL-1β and are inflammatory, MHC-II<sup>pos</sup>; PD-L1<sup>pos</sup> neutrophils are regulatory

## IN SUMMARY

Dual “brake” and “accelerator” functions exerted by the two neutrophil subsets on Mtb infection in the lung. Two functionally distinct neutrophil subsets are recruited to the lungs in response to mycobacterial infection. Classic [MHC-II-, PD-L1⁹] neutrophils produce high levels of inflammasome-dependent IL-1β in the lungs in response to virulent mycobacteria and act as an “accelerator” of deleterious inflammation, which is highly exacerbated in IFN-γR-/- mice. Conversely, regulatory [MHC-II+, PD-L1hi] neutrophils act as a “brake” of inflammation by suppressing T-cell proliferation and IFN-γ production. This regulation depends on PD-L1 surface expression, controlled by IFN-γR signaling in neutrophils.

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## 2- Is PD-L1 regulated by other signals ?

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## 3- Can MHC-II<sup>pos</sup> regulatory neutrophils dampen inflammation in vivo?

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MHC-II<sup>pos</sup> neutrophils from WT mice transferred into Mtb-infected IFN-γR-/- mice dampen lung inflammation.

## Next...

* C3HeB/FeJ mice: distribution of regulatory and inflammatory neutrophils in a model with "proper TB granuloma" (see **poster by Doz-Deblauwe et al.**)

* Examine these two neutrophil subsets in TB patients

* Understand their respective roles in inflammatory compounds

production in the lung during TB

## Many thanks to

The mouse team of the **PFIE** (INRAE, Nouzilly), especially **Corinne Beaugé, Jérôme Pottier & Emilie Lortscher**

**Valérie Quesniaux** (INEM, UMR7355 CNRS, Université d'Orléans, France) **Aim2-/-**, **Gsdmd-/-**, **Nlrp3-/-**, **Csp1/11-/-** mice,

**Alix Sausset and Christelle Rossignol**, from the IMI team (ISP, INRAE, Nouzilly) neutrophil cell sorting and histology.

**Sonia Lacroix-Lamandé** and the AIM team (ISP, INRAE, Nouzilly) Fluidigm Biomark.

**André Rieutord and Hail Aboudagga** (Gustave Roussy Cancer Campus, Villejuif, France) for Anti-PD-L1 Ab (Tecentriq®, atezolizumab)

**Mustapha Si-Tahar and Hervé Watier** (CEPR, UMR 1100, INSERM, Université de Tours, France) for helpful discussions.

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INRAE Centre Val de Loire
UMR1282 Infectiology & Public Health
Route de Crotelles - 37380 Nouzilly France

Bacterial Infections and Immunity of Ruminants

* nathalie.winter@inrae.fr

* emilie.doz-deblauwe@inrae.fr

* badreddine.bounab@inrae.fr

EUR FÉRI

L'EUROPE

s'engage

en région

Centre-Val de Loire

aux États-Unis

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