Role of the chemokine decoy receptor D6 in balancing inflammation, immune activation, and antimicrobial resistance in Mycobacterium tuberculosis infection

Abstract

D6 is a decoy and scavenger receptor for inflammatory CC chemokines. D6-deficient mice were rapidly killed by intranasal administration of low doses of Mycobacterium tuberculosis. The death of D6−/− mice was associated with a dramatic local and systemic inflammatory response with levels of M. tuberculosis colony-forming units similar to control D6-proficient mice. D6-deficient mice showed an increased numbers of mononuclear cells (macrophages, dendritic cells, and CD4 and CD8 T lymphocytes) infiltrating inflamed tissues and lymph nodes, as well as abnormal increased concentrations of CC chemokines (CCL2, CCL3, CCL4, and CCL5) and proinflammatory cytokines (tumor necrosis factor α, interleukin 1β, and interferon γ) in bronchoalveolar lavage and serum. High levels of inflammatory cytokines in D6−/− infected mice were associated with liver and kidney damage, resulting in both liver and renal failure. Blocking inflammatory CC chemokines with a cocktail of antibodies reversed the inflammatory phenotype of D6−/− mice but led to less controlled growth of M. tuberculosis. Thus, the D6 decoy receptor plays a key role in setting the balance between antimicrobial resistance, immune activation, and inflammation in M. tuberculosis infection.

D6 and the atypical chemokine receptor family: Novel regulators of immune and inflammatory processes

“…These data, together, show that D6-null mice are unable to effectively control pulmonary inflammation in this murine model of airways disease. Interestingly, this enhanced inflammatory chemokine and cell infiltration into the D6-null lungs is associated with decreased airway responses to methacholine compared with that seen in WT mice.More recently, studies into the role of D6 in murine model of Mycobacterium tuberculosis infection have revealed that D6-null mice are significantly more susceptible to death following intranasal administration of M. tuberculosis than their WT counterparts [67]. This is associated with a dramatic local and systemic inflammatory response that leads to widespread tissue damage that precipitates liver and renal failure.…”

Recognition Versus Adaptive Up-regulation and Degradation of CC Chemokines by the Chemokine Decoy Receptor D6 Are Determined by Their N-terminal Sequence

“…Ϫ/Ϫ mice have demonstrated that its chemokine scavenging activity attenuates the severity of inflammation in different experimental models (12,(15)(16)(17) and suppresses inflammation-driven tumor development (18) (19).…”

Tuning inflammation in tuberculosis: the role of decoy receptors

“…The increased recruitment of inflammatory cells in different organs of receptor-deficient mice may cause massive, local and systemic production of pro-inflammatory cytokines, such as TNFa and IL-1b and chemokines, which ultimately cause tissue damage, as suggested by date reported in the literature [47,49]. Accordingly, lung mononuclear cells from M. tuberculosisinfected D6 À/À and Tir8 À/À mice produced larger amounts of these cytokines, and, most important and relevant to the observed phenotype, abundantly higher levels of TNFa and IL-1b were found in bronchoalveolar lavage and sera of M. tuberculosis-infected D6-and Tir-8 deficient mice.…”

“…The expression levels of the D6 receptor, mainly confined on lymphatic endothelial cells, is not modified in human lungs and lymph nodes of individuals infected with M. tuberculosis [49], as well as in lungs, liver and spleen of mice infected with M. tuberculosis infection [49].…”

“…This lack of specific knowledge on the biological role of decoy receptors in the resolution of infectioninduced inflammatory responses, prompted us to investigate the role of the D6 and Tir8 receptors in mice infected intranasally with M. tuberculosis [49], known to cause a chronic inflammatory response.…”