title: 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
authors: G
authors: Nouailles
authors: Anca
authors: A
authors: Dorhoi
authors: Markus
authors: M
authors: Koch
authors: Jens
authors: J
authors: Zerrahn
authors: January
authors: J
authors: Weiner
authors: Kellen C
authors: KC
authors: Faé
authors: Frida
authors: F
authors: Arrey
authors: Stefanie
authors: S
authors: Kuhlmann
authors: Silke
authors: S
authors: Bandermann
authors: Delia
authors: D
authors: Loewe
authors: Hans-Joachim
authors: HJ
authors: Mollenkopf
authors: Alexis
authors: A
authors: Vogelzang
authors: Catherine
authors: C
authors: Meyer-Schwesinger
authors: Hans-Willi
authors: HW
authors: Mittrücker
authors: Gayle
authors: G
authors: McEwen
authors: Stefan H E
authors: SH
authors: Kaufmann
mesh_terms: D056809:Alveolar Epithelial Cells / Q000276:immunology* / Q000378:metabolism / Q000382:microbiology; D000818:Animals; D002460:Cell Line; D054365:Chemokine CXCL5 / Q000502:physiology*; D007249:Inflammation / Q000378:metabolism / Q000382:microbiology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009169:Mycobacterium tuberculosis / Q000276:immunology*; D020556:Neutrophil Infiltration; D009504:Neutrophils / Q000276:immunology* / Q000382:microbiology; D023063:Receptors, Interleukin-8B / Q000378:metabolism; D013601:T-Lymphocytes / Q000276:immunology / Q000382:microbiology; D051195:Toll-Like Receptor 2 / Q000378:metabolism; D015533:Transcriptional Activation; D014397:Tuberculosis, Pulmonary / Q000276:immunology* / Q000378:metabolism / Q000473:pathology
chemical_list: D054365:Chemokine CXCL5; C094739:Cxcl5 protein, mouse; D023063:Receptors, Interleukin-8B; C493486:Tlr2 protein, mouse; D051195:Toll-Like Receptor 2