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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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 1

Neutrophil depletion during chronic TB improves Mtb control.

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Neutrophil depletion during chronic TB improves Mtb control. (A) The num...
(A) The numbers of blood neutrophils from Rhesus macaques with ATB (n = 8) or LTBI (n = 10) were measured at dpi following Mtb infection or at necropsy (N). B6 mice (n = 5–13) were aerosol infected with approximately 100 CFU Mtb HN878. (B) Neutrophil accumulation was determined by flow cytometry at dpi. B6 mice were infected with Mtb HN878 and administered IgG (n = 5–10) or 1A8 (n = 5–10, 300-μg/dose) i.p. every other day. (C) Bacterial burden in the lung and spleen was determined by plating on 21 dpi. (D) Lung homogenates were analyzed for G-CSF protein expression by ELISA on 21 dpi. (E) Pulmonary inflammation was quantified on formalin-fixed, paraffin-embedded (FFPE) lung sections from 21 dpi samples stained with H&E. B6 mice were infected with HN878 and administered IgG (n = 4–5) or 1A8 (n = 4–5, 300-μg/dose) i.p. every other day. (F) Bacterial burden in the lung and spleen was determined by plating on 106 dpi. (G) Lung homogenates were analyzed to measure levels of IL-6 and TNF-α proteins at 106 dpi using Luminex assays. (H) Pulmonary inflammation was quantified on FFPE lung sections from 106 dpi tissues stained with H&E. Figures depict 1 experiment representative of 2 or combined data from multiple experiments. Data points represent the mean ± SEM of values. (A) 2-way ANOVA; (B) Student’s t test between 0 and indicated dpi; (C–G) Student’s t test between isotype- and 1A8-treated mice. *P ≤ 0.05; **P ≤ 0.01; ***P ≤ 0.001; ****P ≤ 0.0001.