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

J Clin Invest. 2014 Mar;124(3):1268-82. doi: 10.1172/JCI72030. Epub 2014 Feb 10.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alveolar Epithelial Cells / immunology*
  • Alveolar Epithelial Cells / metabolism
  • Alveolar Epithelial Cells / microbiology
  • Animals
  • Cell Line
  • Chemokine CXCL5 / physiology*
  • Inflammation / metabolism
  • Inflammation / microbiology
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Mycobacterium tuberculosis / immunology*
  • Neutrophil Infiltration
  • Neutrophils / immunology*
  • Neutrophils / microbiology
  • Receptors, Interleukin-8B / metabolism
  • T-Lymphocytes / immunology
  • T-Lymphocytes / microbiology
  • Toll-Like Receptor 2 / metabolism
  • Transcriptional Activation
  • Tuberculosis, Pulmonary / immunology*
  • Tuberculosis, Pulmonary / metabolism
  • Tuberculosis, Pulmonary / pathology


  • Chemokine CXCL5
  • Cxcl5 protein, mouse
  • Receptors, Interleukin-8B
  • Tlr2 protein, mouse
  • Toll-Like Receptor 2

Associated data

  • GEO/GSE43337