Mycobacteria induce TPL-2 mediated IL-10 in IL-4-generated alternatively activated macrophages

Soumya Chatterjee, Kawsar R. Talaat, Emily E. van Seventer, Carl G. Feng, Alan L. Scott, Anne Jedlicka, Amanda Dziedzic, Thomas B. Nutman

Research output: Research - peer-reviewArticle

Abstract

IL-4 drives expansion of Th2 cells that cause generation of alternatively activated macrophages (AAMs). Filarial infections are established early in life, induce increased IL-4 production are co-endemic with tuberculosis (TB). We sought to understand, therefore, how mycobacteria are handled in the context of IL-4-induced AAM. Comparing IL-4 generated in vitro monocyte derived human AAMs to LPS and IFN-γ generated classically macrophages (CAMs), both infected with mycobacteria (BCG), we demonstrated increased early BCG uptake and increased IL-10 production in AAMs compared to CAMs. We further demonstrated that increased IL-10 production is mediated by upregulation of tumor progression locus 2 (TPL-2), an upstream activator of extracellular signal related kinases (ERKs) in AAMs but not in CAMs, both at the transcript as well as the protein level. Pharmacologic inhibition of TPL-2 significantly diminished IL-10 production only in BCG-infected AAMs. Finally, we validated our findings in an in vivo C57Bl/6 model of filarial infection, where an exaggerated Th2 induced lung-specific alternative activation led to TPL-2 and IL-10 upregulation on subsequent TB infection. These data show that in response to mycobacterial infection, IL-4 generated AAMs in chronic filarial infections have impaired immune responses to TB infection by increasing IL-10 production in a TPL-2 mediated manner.

LanguageEnglish (US)
Article numbere0179701
JournalPLoS ONE
Volume12
Issue number6
DOIs
StatePublished - Jun 1 2017

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Mycobacterium
interleukin-4
interleukin-10
macrophages
loci
neoplasms
Interleukin-4
Interleukin-10
Macrophages
Neoplasms
Tumors
Infection
infection
tuberculosis
Mycobacterium bovis
Tuberculosis
Up-Regulation
mycobacterial diseases
monocytes
phosphotransferases (kinases)

ASJC Scopus subject areas

  • Medicine(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)

Cite this

Mycobacteria induce TPL-2 mediated IL-10 in IL-4-generated alternatively activated macrophages. / Chatterjee, Soumya; Talaat, Kawsar R.; van Seventer, Emily E.; Feng, Carl G.; Scott, Alan L.; Jedlicka, Anne; Dziedzic, Amanda; Nutman, Thomas B.

In: PLoS ONE, Vol. 12, No. 6, e0179701, 01.06.2017.

Research output: Research - peer-reviewArticle

Chatterjee, Soumya ; Talaat, Kawsar R. ; van Seventer, Emily E. ; Feng, Carl G. ; Scott, Alan L. ; Jedlicka, Anne ; Dziedzic, Amanda ; Nutman, Thomas B./ Mycobacteria induce TPL-2 mediated IL-10 in IL-4-generated alternatively activated macrophages. In: PLoS ONE. 2017 ; Vol. 12, No. 6.
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