S100A8/A9 regulates CD11b expression and neutrophil recruitment during chronic tuberculosis
Ninecia R. Scott, … , Joaquín Zúñiga, Shabaana A. Khader
Ninecia R. Scott, … , Joaquín Zúñiga, Shabaana A. Khader
Published March 5, 2020
Citation Information: J Clin Invest. 2020;130(6):3098-3112. https://doi.org/10.1172/JCI130546.
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Research Article Immunology Infectious disease

S100A8/A9 regulates CD11b expression and neutrophil recruitment during chronic tuberculosis

Abstract

Neutrophil accumulation is associated with lung pathology during active tuberculosis (ATB). However, the molecular mechanism or mechanisms by which neutrophils accumulate in the lung and contribute to TB immunopathology are not fully delineated. Using the well-established mouse model of TB, our new data provide evidence that the alarmin S100A8/A9 mediates neutrophil accumulation during progression to chronic TB. Depletion of neutrophils or S100A8/A9 deficiency resulted in improved Mycobacterium tuberculosis (Mtb) control during chronic but not acute TB. Mechanistically, we demonstrate that, following Mtb infection, S100A8/A9 expression is required for upregulation of the integrin molecule CD11b specifically on neutrophils, mediating their accumulation during chronic TB disease. These findings are further substantiated by increased expression of S100A8 and S100A9 mRNA in whole blood in human TB progressors when compared with nonprogressors and rapidly decreased S100A8/A9 protein levels in the serum upon TB treatment. Furthermore, we demonstrate that S100A8/A9 serum levels along with chemokines are useful in distinguishing between ATB and asymptomatic Mtb-infected latent individuals. Thus, our results support targeting S100A8/A9 pathways as host-directed therapy for TB.

Authors

Ninecia R. Scott, Rosemary V. Swanson, Noor Al-Hammadi, Racquel Domingo-Gonzalez, Javier Rangel-Moreno, Belinda A. Kriel, Allison N. Bucsan, Shibali Das, Mushtaq Ahmed, Smriti Mehra, Puthayalai Treerat, Alfredo Cruz-Lagunas, Luis Jimenez-Alvarez, Marcela Muñoz-Torrico, Karen Bobadilla-Lozoya, Thomas Vogl, Gerhard Walzl, Nelita du Plessis, Deepak Kaushal, Thomas J. Scriba, Joaquín Zúñiga, Shabaana A. Khader

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Figure 6

S100A8/A9 regulates CD11b expression on neutrophils.

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S100A8/A9 regulates CD11b expression on neutrophils. Bone marrow neutrop...
Bone marrow neutrophils were isolated and infected with mCherry-labeled HN878 (MOI of 1) for 3 hours. (A) Mtb uptake by neutrophils was determined in B6 (n = 5) and S100A9KO (n = 5) neutrophils using flow cytometry. (B) MFI of CD11b, Gr-1, and CD18 expression on uninfected (UI) and highly infected (Mtbhi) neutrophils was determined by flow cytometry. Bone marrow neutrophils were isolated and infected with HN878 (MOI of 1) for 3 hours. (C) Expression of phagocytic markers quantitated via RT-PCR and (D) TNF-α and IL-6 levels as quantitated by Luminex assays. Bone marrow neutrophils were isolated from B6 (n = 5) and S100A9KO (n = 5) mice and infected with HN878 (MOI of 1) for 1 hour. (E) Neutrophil chemotactic activity was assayed against gravity controls (Grav.) (circles) or supernatants from infected epithelial cells (Supe.) (squares). Neutrophils from B6 mice were left untreated or treated with HK Mtb, Mtb CFP, and Mtb CW. (F) CD11b and Gr-1 MFI were assessed using flow cytometry. Bone marrow neutrophils from IKKfl/fl LysMCre mice (n = 5) and IKKfl/fl (n = 5) mice were infected with Mtb (MOI 1). (G) Mtb uptake and MFI of CD11b and Gr-1 expression on uninfected or infected neutrophils was determined by flow cytometry. Figures depict 1 experiment representative of 2 or combined data from multiple experiments. Data points represent the mean ± SEM of values. (A–G) Student’s t test. *P ≤ 0.05; **P ≤ 0.01; ***P ≤ 0.001; ****P ≤ 0.0001.