CXCL1 Regulates Pulmonary Host Defense to <i>Klebsiella</i> Infection via CXCL2, CXCL5, NF-κB, and MAPKs

Cai, Shanshan; Batra, Sanjay; Lira, Sérgio A.; Kolls, Jay K.; Jeyaseelan, Samithamby

doi:10.4049/jimmunol.0903843

Cited by 112 publications

(166 citation statements)

References 34 publications

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“…We demonstrate that PMN recruitment to the lung following a high-dose M. tuberculosis infection caused exaggerated inflammation with fatal consequences due to tissue inflammation rather than increased bacterial load. The detrimental effects of CXCL5 and CXCR2 in TB stand in marked contrast to several reports on the pro- tective role of CXCR2-dependent PMN recruitment in acute bacterial infections (30,34,35). This discrepancy might best be explained by differential dependencies on PMNs for bacterial clearance.…”

Section: Discussionmentioning

confidence: 67%

“…show impaired PMN recruitment into airspaces (30,37). Depletions of CXCL2 or CXCL1 during pulmonary Legionella pneumoniae and Pseudomonas aeruginosa infection reduce PMN recruitment modestly, but blockage of CXCR2 causes pronounced reduction in PMNs followed by increased mortality (35,36).…”

Section: Discussionmentioning

confidence: 99%

“…Using BM chimeric mice and Klebsiella pneumoniae infection, Cai et al showed that CXCL1 was expressed by both radioresistant and radiosensitive cells (30). CXCL1 and CXCL2 are secreted by myeloid cells, such as macrophages and PMNs (31), and their importance in PMN recruitment to inflamed lungs is well appreciated in various infectious diseases (30,(32)(33)(34)(35)(36). CXCL15, which is produced by bronchial epithelial cells (29), contributes to pulmonary defense against K. pneumoniae infection (37).…”

Section: Introductionmentioning

confidence: 99%

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

Nouailles¹,

Dorhoi²,

Koch³

et al. 2014

J. Clin. Invest.

187

185

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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 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.

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Section: Discussionmentioning

confidence: 67%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

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

Nouailles¹,

Dorhoi²,

Koch³

et al. 2014

J. Clin. Invest.

187

185

View full text Add to dashboard Cite

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“…Donor and recipient mice (6-8 wk old) were used to generate chimeras, as described earlier (30,31). We found that more than 90% of blood leukocytes were derived from donor mice at the time the mice were used for experiments (data not shown).…”

Section: Bone Marrow Transplantationmentioning

confidence: 94%

Role of CXCL5 in Leukocyte Recruitment to the Lungs during Secondhand Smoke Exposure

Balamayooran¹,

Batra²,

Cai³

et al. 2012

Am J Respir Cell Mol Biol

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Chronic obstructive pulmonary disease (COPD) is the third leading cause of mortality in the United States. The major cause of COPD is cigarette smoking. Extensive leukocyte influx into the lungs, mediated by chemokines, is a critical event leading to COPD. Although both resident and myeloid cells secrete chemokines in response to inflammatory stimuli, little is known about the role of epithelial-derived chemokines, such as CXC chemokine ligand (CXCL)5, in the pathogenesis of cigarette smoke-induced inflammation. To explore the role of CXCL5, we generated CXCL5 genedeficient mice and exposed them to secondhand smoke (SHS) for 5 hours/day for 5 days/week up to 3 weeks (subacute exposure). We observed a reduced recruitment of leukocytes to the lungs of CXCL5 2/2 mice compared with their wild-type (WT) counterparts, and noted that macrophages comprised the predominant leukocytes recruited to the lungs. Irradiation experiments performed on CXCL5 2/2 or WT mice transplanted with WT or CXCL5 2/2 bone marrow revealed that resident but not hematopoietic cell-driven CXCL5 is important for mediating SHS-induced lung inflammation. Interestingly, we observed a significant reduction of monocyte chemotactic protein-1 (MCP-1/CC chemokine ligand 2) concentrations in the lungs of CXCL5 2/2 mice. The instillation of recombinant MCP-1 in CXCL52/2 mice reversed macrophage recruitment. Our results also show the reduced activation of NF-kB/p65 in the lungs, as well as the attenuated activation of C-Jun N-terminal kinase, p42/44, and p38 mitogen-activated protein kinases and the expression of intercellular adhesion molecule-1 in the lungs of SHS-exposed CXCL5 2/2 mice. Our findings suggest an important role for CXCL5 in augmenting leukocyte recruitment in SHS-induced lung inflammation, and provide novel insights into CXCL5-driven pathogenesis.Keywords: smoke; CXCL5/LIX; macrophages; chemokines; cytokines Chronic obstructive pulmonary disease (COPD) is the third leading cause of death in the United States (1-3). According to recent reports, the prevalence of COPD in the United States involves more than 12 million, with an annual mortality of 120,000 (1-3). COPD is an irreversible disease characterized by airway inflammation (chronic bronchitis) and airspace enlargement, along with the destruction of lung parenchyma (emphysema) (4, 5). Although the molecular and cellular mechanisms that contribute to the development of COPD are not well understood, substantial recruitment and activation of inflammatory cells into the airspaces and lung parenchyma has been documented in humans with COPD and implicated in its pathogenesis (4, 5).Cigarette smoking accounts for most of the debilitating effects of COPD, but other environmental risk factors include air pollution and chronic occupational exposure to various dusts (6). Why only a small proportion (10-20%) of smokers develops COPD remains unclear (7). Cigarette smoke (CS) contains more than 4,700 chemicals (8), and is a powerful inducer of inflammatory mediators, including oxidants and proteases,...

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“…CXCL1 is a pleiotropic chemokine contributing to the recruitment of neutrophils, cell proliferation, tumor angiogenesis, invasion and metastasis. The importance of CXCL1 in neutrophil-dependent bacterial elimination has been demonstrated in a lung experimental system (23,24). Accordingly, flagellindependent CXCL1 induction in SGECs should have an antimicrobial effect.…”

Section: Discussionmentioning

confidence: 99%

Functional expression of TLR5 in murine salivary gland epithelial cells

Iwasa

Ota

Nishio³

et al. 2016

J Oral Sci

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CXCL1 Regulates Pulmonary Host Defense to Klebsiella Infection via CXCL2, CXCL5, NF-κB, and MAPKs

Cited by 112 publications

References 34 publications

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

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

Role of CXCL5 in Leukocyte Recruitment to the Lungs during Secondhand Smoke Exposure

Functional expression of TLR5 in murine salivary gland epithelial cells

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