Toll-like receptor-induced arginase 1 in macrophages thwarts effective immunity against intracellular pathogens.
Toll-like receptor (TLR) signaling in macrophages is required for antipathogen responses, including the biosynthesis of nitric oxide from arginine, and is essential for immunity to Mycobacterium tuberculosis, Toxoplasma gondii and other intracellular pathogens. Here we report a 'loophole' in the TLR pathway that is advantageous to these pathogens. Intracellular pathogens induced expression of the arginine hydrolytic enzyme arginase 1 (Arg1) in mouse macrophages through the TLR pathway. In contrast to diseases dominated by T helper type 2 responses in which Arg1 expression is greatly increased by interleukin 4 and 13 signaling through the transcription factor STAT6, TLR-mediated Arg1 induction was independent of the STAT6 pathway. Specific elimination of Arg1 in macrophages favored host survival during T. gondii infection and decreased lung bacterial load during tuberculosis infection.
El Kasmi
Karim C
KC
Department of Infectious Diseases, St. Jude Children's Research Hospital, Memphis, Tennessee 38015, USA.
Qualls
Joseph E
JE
Pesce
John T
JT
Smith
Amber M
AM
Thompson
Robert W
RW
Henao-Tamayo
Marcela
M
Basaraba
Randall J
RJ
König
Till
T
Schleicher
Ulrike
U
Koo
Mi-Sun
MS
Kaplan
Gilla
G
Fitzgerald
Katherine A
KA
Tuomanen
Elaine I
EI
Orme
Ian M
IM
Kanneganti
Thirumala-Devi
TD
Bogdan
Christian
C
Wynn
Thomas A
TA
Murray
Peter J
PJ
D000818:Animals; D001119:Arginase / Q000276:immunology* / Q000378:metabolism; D001424:Bacterial Infections / Q000276:immunology*; D022782:CCAAT-Enhancer-Binding Protein-beta / Q000276:immunology / Q000378:metabolism; D015151:Immunoblotting; D007150:Immunohistochemistry; D008264:Macrophages / Q000276:immunology* / Q000382:microbiology*; D051379:Mice; D018345:Mice, Knockout; D053594:Myeloid Differentiation Factor 88 / Q000276:immunology / Q000378:metabolism; D050800:STAT6 Transcription Factor / Q000276:immunology / Q000378:metabolism; D051193:Toll-Like Receptors / Q000276:immunology* / Q000378:metabolism
D022782:CCAAT-Enhancer-Binding Protein-beta; D053594:Myeloid Differentiation Factor 88; D050800:STAT6 Transcription Factor; D051193:Toll-Like Receptors; D001119:Arginase