Arginine Usage in Mycobacteria-Infected Macrophages Depends on Autocrine-Paracrine Cytokine Signaling

Abstract

Nitric oxide (NO) produced by macrophages is toxic to host tissues and invading pathogens and its regulation is therefore essential to suppress host cytotoxicity. Macrophage arginase 1 (Arg1) inhibits the production of NO by competing with NO synthases for arginine, the common substrate of NO synthases and arginases. Two signal transduction pathways control the production of Arg1 in macrophages. First, a pathway dependent on the Toll-like receptor (TLR) adaptor protein myeloid differentiation marker 88 (MyD88) induces the expression of Arg1 in intracellular infections, whereas a second pathway, which is dependent on signal transducer and activator of transcription 6 (STAT6) is required for the expression of Arg1 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 the expression of Arg1 in an autocrine-paracrine manner. We further established that Arg1 expression was controlled by the MyD88-dependent production of IL-6, IL-10, and G-CSF rather than by cell-intrinsic MyD88 signaling to Arg1. Our data reveal that the MyD88-dependent pathway that induces expression of Arg1 after infection by mycobacteria requires the activation of STAT3 and may result in the development of an immunosuppressive niche in granulomas because of the induced production of Arg1 in surrounding uninfected macrophages.* This manuscript has been accepted for publication in Science Signaling. This version has not undergone final editing. Please refer to the complete version of record at http://www.sciencesignaling.org/. The manuscript may not be reproduced or used in any manner that does not fall within the fair use provisions of the

The E3 Ubiquitin Ligase Neuregulin Receptor Degradation Protein 1 (Nrdp1) Promotes M2 Macrophage Polarization by Ubiquitinating and Activating Transcription Factor CCAAT/Enhancer-binding Protein β (C/EBPβ)

“…In addition, because C/EBP␤ is required for basal expression of Arg1 in macrophages (28), the steady interaction between Nrdp1 and C/EBP␤ may account for the constitutive up-regulation of Arg1 in Nrdp1-TG macrophages. Recently, El Kasmi et al (29) demonstrated that Mycobacterium tuberculosis-induced expression of Arg1 in macrophages depends on C/EBP␤ signaling but is independent of the STAT6 signaling, and Mycobacteriuminduced IL-6, IL-10, and G-CSF production accounts for the increased Arg1 expression in an autocrine-paracrine manner by activating the STAT3-signaling pathway (30), which is consistent with our results and establishes the crucial role of C/EBP␤ in the expression of Arg1 gene.…”

A Distal Enhancer in Il12b Is the Target of Transcriptional Repression by the STAT3 Pathway and Requires the Basic Leucine Zipper (B-ZIP) Protein NFIL3

“…2A, NFIL3 and Bcl-3). We attribute the LPS-mediated expression of each mRNA predominantly to aurocrine-paracrine IL-10 production following LPS stimulation, although other secreted factors such as IL-6 could also potentially contribute to the delayed expression kinetics of each mRNA (37,39). To test this idea directly, we isolated BMDMs from control or Stat3 flox/flox ;Tie2-cre mice that have a Ͼ95% deletion of STAT3 in primary macrophages.…”

“…PDMs were isolated following intraperitoneal injection of thioglycollate as described (36,37). Gut and spleen CD11b ϩ cells were isolated by magnetic bead purification (Miltenyi Biotec).…”

Differential Requirements for l-Citrulline and l-Arginine during Antimycobacterial Macrophage Activity

“…This process can be interrupted by arginase activity, which hydrolyzes L-arginine to L-ornithine and urea, thereby competing with iNOS for bioavailable L-arginine. Similar to iNOS, type 1 arginase (Arg1) is induced in human MFs within TB granulomas and in the lungs of mice infected with M. bovis BCG (16)(17)(18)(19), suggesting substrate competition for L-arginine in vivo. Indeed, mice lacking Arg1 in MFs make more NO and clear M. tuberculosis faster than do control mice (20).…”