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 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.

Helminth-induced arginase-1 exacerbates lung inflammation and disease severity in tuberculosis

“…Interestingly, we found that Arg1 mRNA was among the top 10 genes differentially expressed in mice with SI, when compared with genes expressed in lungs of mice with enhanced Mtb control (Supplemental Table 3 and Figure 7A). In support of recently published studies (14,25), mRNA for inflammatory molecules such as S100a8 and S100a9, and chemokines associated with neutrophilic accumulation, were also increased in the lungs of mice with SI at the mRNA level (Supplemental Table 3). The increased expression of Arg1 mRNA was confirmed by RT-PCR ( Figure 7B).…”

CXCL5 Drives Neutrophil Recruitment in TH17-Mediated GN

“…IL-17A-deficient mice were provided by Yoichiro Iwakura (University of Tokyo, Tokyo, Japan), CXCL5-deficient mice were provided by the Max Plank Institute for Infection Biology (Berlin, Germany) 43 and CXCL1-deficient mice were provided by S. Lira (Mount Sinai Hospital, New York, NY). All KO mice were backcrossed to the C57BL/6 background for at least 10 generations.…”

Efferocytosis and extrusion of leukocytes determine the progression of early mycobacterial pathogenesis

“…Although macrophages are the main cell type commonly associated with mycobacterial infection, a growing body of evidence is showing that other phagocytic cells also play a major role during mycobacterial infection (Berry et al, 2010;Lowe et al, 2012;Nouailles et al, 2014;Srivastava et al, 2014). In the lungs of animals infected with Mtb, several cell types are found to be recruited and to contain bacteria.…”