Damping excessive inflammation and tissue damage in Mycobacterium tuberculosis infection by Toll IL-1 receptor 8/single Ig IL-1-related receptor, a negative regulator of IL-1/TLR signaling.
Toll IL-1R 8/single Ig IL-1-related receptor (TIR8/SIGIRR) is a member of the IL-1R family, expressed by epithelial tissues and immature dendritic cells, and is regarded as a negative regulator of TLR/IL-1R signaling. Tir8-deficient mice were rapidly killed by intranasal administration of low doses of Mycobacterium tuberculosis, despite controlling efficiently the number of viable bacilli in different organs. Tir8(-/-)-infected mice showed an increased number of neutrophils and macrophages in the lungs; however, mycobacteria-specific CD4 and CD8 T cells were similar in Tir8(-/-) and Tir8(+/+) mice. Exaggerated mortality of Tir8(-/-) mice was due to massive liver necrosis and was accompanied by increased levels of IL-1beta and TNF-alpha in lung mononuclear cells and serum, as well as by increased production of IL-1beta and TNF-alpha by M. tuberculosis-infected dendritic cells in vitro. Accordingly, blocking IL-1beta and TNF-alpha with a mix of anti-cytokine Abs, significantly prolonged survival of Tir8(-/-) mice. Thus, TIR8/SIGIRR plays a key role in damping inflammation and tissue damage in M. tuberculosis infection.
Garlanda
Cecilia
C
Dipartimento di Biopatologia e Metodologie Biomediche, Università di Palermo, Corso Tukory 211, 90134 Palermo, Italy.
Di Liberto
Diana
D
Vecchi
Annunciata
A
La Manna
Marco P
MP
Buracchi
Chiara
C
Caccamo
Nadia
N
Salerno
Alfredo
A
Dieli
Francesco
F
Mantovani
Alberto
A
D000818:Animals; D000906:Antibodies / Q000494:pharmacology; D002465:Cell Movement; D016207:Cytokines / Q000378:metabolism; D003713:Dendritic Cells / Q000276:immunology / Q000382:microbiology; D007249:Inflammation / Q000235:genetics / Q000276:immunology / Q000382:microbiology; D007375:Interleukin-1 / Q000037:antagonists & inhibitors / Q000097:blood / Q000378:metabolism; D053583:Interleukin-1beta / Q000037:antagonists & inhibitors / Q000097:blood / Q000378:metabolism*; D008099:Liver / Q000276:immunology / Q000473:pathology; D008168:Lung / Q000276:immunology; D016676:Macrophages, Alveolar / Q000276:immunology; D051379:Mice; D008817:Mice, Mutant Strains; D009169:Mycobacterium tuberculosis; D009336:Necrosis; D009504:Neutrophils / Q000276:immunology; D017472:Receptors, Interleukin-1 / Q000235:genetics / Q000502:physiology*; D015398:Signal Transduction; D051193:Toll-Like Receptors / Q000378:metabolism; D014397:Tuberculosis, Pulmonary / Q000235:genetics* / Q000276:immunology; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors / Q000097:blood / Q000378:metabolism
D000906:Antibodies; D016207:Cytokines; D007375:Interleukin-1; D053583:Interleukin-1beta; D017472:Receptors, Interleukin-1; D051193:Toll-Like Receptors; D014409:Tumor Necrosis Factor-alpha; C484529:SIGIRR protein, mouse