Role of the chemokine decoy receptor D6 in balancing inflammation, immune activation, and antimicrobial resistance in Mycobacterium tuberculosis infection.
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 alpha, interleukin 1beta, and interferon gamma) 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.
Di Liberto
Diana
D
Dipartimento di Biopatologia e Metodologie Biomediche, Università di Palermo, 90134 Palermo, Italy.
Locati
Massimo
M
Caccamo
Nadia
N
Vecchi
Annunciata
A
Meraviglia
Serena
S
Salerno
Alfredo
A
Sireci
Guido
G
Nebuloni
Manuela
M
Caceres
Neus
N
Cardona
Pere-Joan
PJ
Dieli
Francesco
F
Mantovani
Alberto
A
D000818:Animals; D000890:Anti-Infective Agents / Q000494:pharmacology*; D024881:Drug Resistance, Bacterial; D007107:Immune System; D007249:Inflammation; D007371:Interferon-gamma / Q000096:biosynthesis; D053583:Interleukin-1beta / Q000096:biosynthesis; D008198:Lymph Nodes / Q000382:microbiology; D051379:Mice; D008822:Mice, Transgenic; D008954:Models, Biological; D009169:Mycobacterium tuberculosis / Q000378:metabolism*; D010641:Phenotype; D054447:Receptors, CCR10 / Q000502:physiology*; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis; D000097628:Chemokine Receptor D6
D000890:Anti-Infective Agents; D007371:Interferon-gamma; D053583:Interleukin-1beta; D054447:Receptors, CCR10; D014409:Tumor Necrosis Factor-alpha; D000097628:Chemokine Receptor D6