CCR7 Modulates Pulmonary and Lymph Node Inflammatory Responses in Cigarette Smoke-Exposed Mice

Abstract

Peribronchial lymphoid follicles have recently been identified as one of the hallmark features of (severe) chronic obstructive pulmonary disease (COPD). However, little is known about the relative contribution of peribronchial lymphoid follicles vs mediastinal lymph nodes in inflammatory responses in COPD patients and animal models. In a murine model of COPD, we studied inflammatory responses in airways, lungs, and mediastinal lymph nodes of wild-type (WT) vs CCR7 knockout (CCR7−/−) mice upon subacute or chronic exposure to cigarette smoke (CS). Although crucial for the organization of the secondary lymphoid organs, CCR7 was not required for the development of chronic CS-induced pulmonary lymphoid follicles. Moreover, T cell numbers were significantly increased in airways and lungs of air-exposed CCR7−/− mice, and they continued to increase upon chronic CS exposure. Unexpectedly, subacute CS-induced inflammation in airways and lungs, including airway neutrophilia and the recruitment of inflammatory-type CD11b+ dendritic cells, depended greatly on CCR7. In the draining lymph nodes, chronic CS exposure induced CCR7-dependent recruitment of airway-derived dendritic cells, accompanied by increases in CD4+ and CD8+ T cells. Correspondingly, CS exposure up-regulated mRNA expression of CCR7 ligands CCL19 and CCL21-Ser in lymph nodes of WT mice, but not CCR7−/− mice. In the lungs of WT mice, chronic CS exposure significantly increased CCL19 mRNA and protein. Furthermore, double staining for CCL19 and pro-surfactant protein C showed that alveolar type II cells express high levels of CCL19. These data unveil a so far unappreciated role for CCR7 in modulating inflammatory responses in airways and lungs.

Exacerbation of cigarette smoke-induced pulmonary inflammation by Staphylococcus aureus Enterotoxin B in mice

“…The increase in dense lymphoid aggregates in CS/SEB mice correlated nicely with significant increases in CXCL13 (protein levels in BAL fluid, mRNA levels in total lung) (Figure 8A, B) and CCL19 (mRNA levels) expression in CS/SEB mice compared to all other groups (Figure 8E). CCL21 mRNA levels (both isoforms CCL21-Ser and CCL21-Leu) decreased upon CS exposure, confirming previous findings of CCL21 downregulation upon subacute CS exposure [26] and decreased even further in the CS/SEB group. Intriguingly, the CCL21 mRNA levels of both isoforms tended to increase upon sole SEB exposure (Figure 8C, D).…”

“…Primers and FAM/TAMRA probes were synthesized on demand (Sigma-Proligo). Primer/probe sequences and PCR conditions were performed as described previously [26,27]. …”

Role of IL-1α and the Nlrp3/caspase-1/IL-1β axis in cigarette smoke-induced pulmonary inflammation and COPD

“…Bronchoalveolar lavage (BAL) was performed as previously described [15][16][17]. Briefly, lungs were first lavaged using 36300 mL Hank's buffered salt solution (HBSS), which was free of Ca 2+ and Mg 2+ , and supplemented with 1% bovine serum albumin (BSA), followed by 361 mL HBSS supplemented with 0.6 mM EDTA, via a tracheal cannula.…”

Effect of smoking on immunity in human chronic periodontitis

“…Regarding the characterization of smoking, individuals were classified according to the criteria of Tomar and Asma (Tomar and Asma, 2000;Demoor et al, 2009) in non-smokers (NS) and smokers (S). The individuals were asked about the time of their smoking habit in years (SH/years) and how many cigarettes they smoked per day (C/day).…”