CXCL5-secreting pulmonary epithelial cells drive destructive neutrophilic inflammation in tuberculosis
Geraldine Nouailles, … , Gayle McEwen, Stefan H.E. Kaufmann
Geraldine Nouailles, … , Gayle McEwen, Stefan H.E. Kaufmann
Published February 10, 2014
Citation Information: J Clin Invest. 2014;124(3):1268-1282. https://doi.org/10.1172/JCI72030.
View: Text | PDF
Research Article Pulmonology

CXCL5-secreting pulmonary epithelial cells drive destructive neutrophilic inflammation in tuberculosis

Abstract

Successful host defense against numerous pulmonary infections depends on bacterial clearance by polymorphonuclear leukocytes (PMNs); however, excessive PMN accumulation can result in life-threatening lung injury. Local expression of CXC chemokines is critical for PMN recruitment. The impact of chemokine-dependent PMN recruitment during pulmonary Mycobacterium tuberculosis infection is not fully understood. Here, we analyzed expression of genes encoding CXC chemokines in M. tuberculosis–infected murine lung tissue and found that M. tuberculosis infection promotes upregulation of Cxcr2 and its ligand Cxcl5. To determine the contribution of CXCL5 in pulmonary PMN recruitment, we generated Cxcl5–/– mice and analyzed their immune response against M. tuberculosis. Both Cxcr2–/– mice and Cxcl5–/– mice, which are deficient for only one of numerous CXCR2 ligands, exhibited enhanced survival compared with that of WT mice following high-dose M. tuberculosis infection. The resistance of Cxcl5–/– mice to M. tuberculosis infection was not due to heightened M. tuberculosis clearance but was the result of impaired PMN recruitment, which reduced pulmonary inflammation. Lung epithelial cells were the main source of CXCL5 upon M. tuberculosis infection, and secretion of CXCL5 was reduced by blocking TLR2 signaling. Together, our data indicate that TLR2-induced epithelial-derived CXCL5 is critical for PMN-driven destructive inflammation in pulmonary tuberculosis.

Authors

Geraldine Nouailles, Anca Dorhoi, Markus Koch, Jens Zerrahn, January Weiner 3rd, Kellen C. Faé, Frida Arrey, Stefanie Kuhlmann, Silke Bandermann, Delia Loewe, Hans-Joachim Mollenkopf, Alexis Vogelzang, Catherine Meyer-Schwesinger, Hans-Willi Mittrücker, Gayle McEwen, Stefan H.E. Kaufmann

×

Figure 4

M. tuberculosis–specific type 1 T cell response and pathway analysis in Cxcl5–/– mice.

Options: View larger image (or click on image) Download as PowerPoint
M. tuberculosis–specific type 1 T cell response and pathway analysis in...
(A) Frequencies of IFN-γ+TNF-α+ cells among lung CD4 and CD8 T cells and numbers of IFN-γ+TNF-α+ lung CD4 and CD8 T cells after short-term in vitro restimulation with M. tuberculosis–derived peptides determined by flow cytometry (mean ± SEM; npooled ≥ 14 per time point except on day 0, when n = 10). Mice were infected with high-dose (∼500 CFU) M. tuberculosis. Each time point represents pooled data from at least 2 independent experiments. Curve data pooled from a total of 4 independent experiments (2-way ANOVA/Bonferroni post-test) did not reveal significant differences between groups at analyzed time points. (B) Significant selected pathways by SPIA analysis. P values correspond to pGFWER composite and multiple testing–corrected P values from SPIA analysis. Plots show log2 fold changes in gene expression of given pathways between naive and day 21 p.i. WT lungs (horizontal axis) and Cxcl5–/– lungs (vertical axis). Mice were infected with high-dose (∼500 CFUs) M. tuberculosis. Red denotes genes for which log fold change is significantly higher in the KO, and blue denotes genes for which log fold change is significantly higher in the WT. (C) Selected GO terms significant in GO enrichment analysis. P values correspond to significance of GO enrichment, corrected for multiple testing. Colors and axes are as in B.