Arginine usage in mycobacteria-infected macrophages depends on autocrine-paracrine cytokine signaling.
Nitric oxide (NO) produced by macrophages is toxic to host tissues and invading pathogens, and its regulation is essential to suppress host cytotoxicity. Macrophage arginase 1 (Arg1) competes with NO synthases for arginine, a substrate common to both types of enzymes, to inhibit NO production. Two signal transduction pathways control the production of Arg1 in macrophages: One pathway dependent on the Toll-like receptor adaptor protein myeloid differentiation marker 88 (MyD88) induces the expression of Arg1 during intracellular infections, whereas another pathway, which depends on signal transducer and activator of transcription 6 (STAT6), is required for Arg1 expression in alternatively activated macrophages. We found that mycobacteria-infected macrophages produced soluble factors, including interleukin-6 (IL-6), IL-10, and granulocyte colony-stimulating factor (G-CSF), that induced expression of Arg1 in an autocrine-paracrine manner. Arg1 expression was controlled by the MyD88-dependent production of these cytokines rather than by cell-intrinsic MyD88 signaling to Arg1. Our study revealed that the MyD88-dependent pathway that induced the expression of Arg1 after infection by mycobacteria required STAT3 activation and that this pathway may cause the development of an immunosuppressive niche in granulomas because of the induced production of Arg1 in surrounding uninfected macrophages.
Qualls
Joseph E
JE
Department of Infectious Diseases, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
Neale
Geoffrey
G
Smith
Amber M
AM
Koo
Mi-Sun
MS
DeFreitas
Ashley A
AA
Zhang
Huiyuan
H
Kaplan
Gilla
G
Watowich
Stephanie S
SS
Murray
Peter J
PJ
D000818:Animals; D001119:Arginase / Q000378:metabolism*; D001120:Arginine / Q000378:metabolism*; D015152:Blotting, Northern; D015153:Blotting, Western; D016207:Cytokines / Q000494:pharmacology*; D004789:Enzyme Activation / Q000187:drug effects*; D016179:Granulocyte Colony-Stimulating Factor / Q000494:pharmacology; D006652:Histological Techniques; D016753:Interleukin-10 / Q000494:pharmacology; D015850:Interleukin-6 / Q000494:pharmacology; D008264:Macrophages / Q000201:enzymology / Q000382:microbiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009161:Mycobacterium; D053594:Myeloid Differentiation Factor 88 / Q000235:genetics / Q000378:metabolism; D019001:Nitric Oxide Synthase / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D050796:STAT3 Transcription Factor / Q000378:metabolism*; D050800:STAT6 Transcription Factor / Q000378:metabolism; D015398:Signal Transduction / Q000276:immunology*
D016207:Cytokines; D015850:Interleukin-6; C507780:Myd88 protein, mouse; D053594:Myeloid Differentiation Factor 88; D050796:STAT3 Transcription Factor; D050800:STAT6 Transcription Factor; C494087:Stat3 protein, mouse; C494100:Stat6 protein, mouse; D016753:Interleukin-10; D016179:Granulocyte Colony-Stimulating Factor; D001120:Arginine; D019001:Nitric Oxide Synthase; C544448:Arg1 protein, mouse; D001119:Arginase