CCR7 Deficiency Leads to Leukocyte Activation and Increased Clearance in Response to Pulmonary Pseudomonas aeruginosa Infection

Abstract

CCR7 is a chemokine receptor expressed on the surfaces of T cells, B cells, and mature dendritic cells that controls cell migration in response to the cognate ligands CCL19 and CCL21. CCR7 is critical for the generation of an adaptive T cell response. However, the roles of CCR7 in the host defense against pulmonary infection and innate immunity are not well understood. We investigated the role of CCR7 in the host defense against acute pulmonary infection with Pseudomonas aeruginosa. We intranasally infected C57BL/6 mice with P. aeruginosa and characterized the expression of CCR7 ligands and the surface expression of CCR7 on pulmonary leukocytes. In response to infection, expression of CCL19 and expression of CCL21 were oppositely regulated, and myeloid dendritic cells upregulated CCR7 expression. We further examined the effects of CCR7 deficiency on the inflammatory response to P. aeruginosa infection. We infected Ccr7 ؊/؊ and wild-type mice with P. aeruginosa and characterized the accumulation of pulmonary leukocytes, production of proinflammatory mediators, neutrophil activation, and bacterial clearance. CCR7 deficiency led to an accumulation of myeloid dendritic cells and T cells in the lung in response to infection. CCR7 deficiency resulted in higher expression of CD80 and CD86 on dendritic cells; increased production of interleukin-12/23p40 (IL-12/23p40), gamma interferon (IFN-␥), and IL-1␣; increased neutrophil respiratory burst; and, ultimately, increased clearance of acute P. aeruginosa infection. In conclusion, our results suggest that CCR7 deficiency results in a heightened proinflammatory environment in response to acute pulmonary P. aeruginosa infection and contributes to more efficient clearance.

The B Lymphocyte Differentiation Factor (BAFF) Is Expressed in the Airways of Children with CF and in Lungs of Mice Infected with Pseudomonas aeruginosa

“…A previous study, using the PAO1 strain, reported increased expression of CCL19 but not CCL21 on day 1 following P. aeruginosa infection but did not study later time points [8]. The data presented here show that both are upregulated post infection but with differential kinetics, CCL19 levels initially being increased before CCL21, although CCL21 is expressed at higher levels by day 7.…”

Elevated concentrations of CCR7 ligands in patients with eosinophilic pneumonia

“…CCL19 is induced locally in the lung in response to Mycobacterium tuberculosis and Mycobacterium bovis bacillus Calmette‐Guérin infection . CCL19 expression and CCL21 expression are differentially regulated; CCL19 is increased and CCL21 is decreased in the lung after Pseudomonas aeruginosa infection and cigarette smoke exposure . Given that the challenge tests with cigarette smoke or drug induced CCL19 production in the BALF of EP patients in the present study, causative agents may promote CCL19 expression from immature DC and AM.…”

Titanium oxide nanoparticle instillation induces inflammation and inhibits lung development in mice

“…We observed that mRNA of Ccl8 (MCP-2), Spp1 (osteopontin), Cxcl9 (Mig), IL1r2, Ccr5, Ccl24, and Itgam (CD11b, Mac-1) were increased and IL11 and Ccr7 were decreased by TiO 2 NPs. All these genes are probably relevant to the inflammation observed: Ccl8 is a well-known chemotactic agent for monocytes (32), Spp1 has a role in immune regulation and has Th1-cytokine functions (38), Cxcl9 is inducible in macrophages in response to interferon-␥ and may play a role in T cell trafficking (24), IL1r2 inhibits IL-1 activity by acting as a decoy target for IL-1 (11) (suggesting that its increase may be compensatory rather than contributory to pathology), Ccr5 is a receptor for MIP-1␣ and -1␤ and is known to have a role in lung inflammation (5), Ccl24 is strongly chemotactic for eosinophils (43), and Itgam is important in neutrophil recruitment to the lung (26), whereas IL-11 (9) and Ccr7 (13), which were decreased, are known to have a protective role in lung injury and inflammation. We also observed that protein amounts of multiple proinflammatory cytokines (e.g., eotaxin, G-CSF, IL-1␤, IL-2, IL-4, IP-10, M-CSF, MIP-1␣, MIP-1␤, MIP-2, TNF-␣) were increased with TiO 2 NP exposure, whereas VEGF was decreased.…”