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

被引：194

作者：

Nouailles, Geraldine ^{[1
]}

Dorhoi, Anca ^{[1
]}

Koch, Markus ^{[1
]}

Zerrahn, Jens ^{[1
]}

Weiner, January, III ^{[1
]}

Fae, Kellen C. ^{[1
]}

Arrey, Frida ^{[1
]}

Kuhlmann, Stefanie ^{[1
]}

Bandermann, Si Ike ^{[1
]}

Loewe, Delia ^{[1
]}

Mollenkopf, Hans-Joachim ^{[2
]}

Vogelzang, Alexis ^{[1
]}

Meyer-Schwesinger, Catherine ^{[3
]}

Mittrucker, Hans-Willi ^{[4
]}

McEwen, Gayle ^{[1
]}

Kaufmann, Stefan H. E. ^{[1
]}

机构：

[1] Max Planck Inst Infect Biol, Berlin, Germany

[2] Max Planck Inst Infect Biol, Core Facil Microarray, Berlin, Germany

[3] Univ Med Ctr Hamburg Eppendorf, Dept Internal Med 3, Hamburg, Germany

[4] Univ Med Ctr Hamburg Eppendorf, Inst Immunol, Hamburg, Germany

来源：

JOURNAL OF CLINICAL INVESTIGATION | 2014年 / 124卷 / 03期

关键词：

CHEMOKINE RECEPTOR CXCR2; MYCOBACTERIUM-TUBERCULOSIS; HOST-DEFENSE; IMMUNE-RESPONSES; MURINE MODEL; T-CELLS; INFECTION; LUNG; RECRUITMENT; CXCL5;

D O I：

10.1172/JCI72030

中图分类号：

R-3 [医学研究方法]; R3 [基础医学];

学科分类号：

100103 [病原生物学]; 100218 [急诊医学];

摘要：

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 chemokinedependent PMN recruitment during pulm onary 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 Cxc/5(-/-) mice and analyzed their immune response against M. tuberculosis. Both Cxcr2(-/-) mice and Cxc/5(-/-) 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 Cxc/5(-/-) 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.

引用

页码：1268 / 1282

页数：15

共 74 条

[1]

Early inhibition of mycobacterial growth by human alveolar macrophages is not due to nitric oxide [J].