Macrophage pro-inflammatory response to Francisella novicida infection is regulated by SHIP.

Kishore V.L. Parsa, Latha P. Ganesan, Murugesan V.S. Rajaram, Mikhail A. Gavrilin, Ashwin Balagopal, Nrusingh P. Mohapatra, Mark D. Wewers, Larry S. Schlesinger, John S. Gunn, Susheela Tridandapani

Research output: Contribution to journalArticle

Abstract

Francisella tularensis, a Gram-negative facultative intracellular pathogen infecting principally macrophages and monocytes, is the etiological agent of tularemia. Macrophage responses to F. tularensis infection include the production of pro-inflammatory cytokines such as interleukin (IL)-12, which is critical for immunity against infection. Molecular mechanisms regulating production of these inflammatory mediators are poorly understood. Herein we report that the SH2 domain-containing inositol phosphatase (SHIP) is phosphorylated upon infection of primary murine macrophages with the genetically related F. novicida, and negatively regulates F. novicida-induced cytokine production. Analyses of the molecular details revealed that in addition to activating the MAP kinases, F. novicida infection also activated the phosphatidylinositol 3-kinase (PI3K)/Akt pathway in these cells. Interestingly, SHIP-deficient macrophages displayed enhanced Akt activation upon F. novicida infection, suggesting elevated PI3K-dependent activation pathways in absence of SHIP. Inhibition of PI3K/Akt resulted in suppression of F. novicida-induced cytokine production through the inhibition of NFkappaB. Consistently, macrophages lacking SHIP displayed enhanced NFkappaB-driven gene transcription, whereas overexpression of SHIP led to decreased NFkappaB activation. Thus, we propose that SHIP negatively regulates F. novicida-induced inflammatory cytokine response by antagonizing the PI3K/Akt pathway and suppressing NFkappaB-mediated gene transcription. A detailed analysis of phosphoinositide signaling may provide valuable clues for better understanding the pathogenesis of tularemia.

Original languageEnglish (US)
JournalPLoS Pathogens
Volume2
Issue number7
DOIs
StatePublished - Jul 2006
Externally publishedYes

Fingerprint

Francisella
src Homology Domains
Phosphatidylinositol 3-Kinase
Macrophages
Tularemia
Infection
Cytokines
Francisella tularensis
Interleukin-12
Phosphatidylinositols
Genes
myo-inositol-1 (or 4)-monophosphatase
Monocytes
Immunity
Phosphotransferases

ASJC Scopus subject areas

  • Microbiology
  • Parasitology
  • Virology
  • Immunology
  • Genetics
  • Molecular Biology

Cite this

Parsa, K. V. L., Ganesan, L. P., Rajaram, M. V. S., Gavrilin, M. A., Balagopal, A., Mohapatra, N. P., ... Tridandapani, S. (2006). Macrophage pro-inflammatory response to Francisella novicida infection is regulated by SHIP. PLoS Pathogens, 2(7). https://doi.org/10.1371/journal.ppat.0020071

Macrophage pro-inflammatory response to Francisella novicida infection is regulated by SHIP. / Parsa, Kishore V.L.; Ganesan, Latha P.; Rajaram, Murugesan V.S.; Gavrilin, Mikhail A.; Balagopal, Ashwin; Mohapatra, Nrusingh P.; Wewers, Mark D.; Schlesinger, Larry S.; Gunn, John S.; Tridandapani, Susheela.

In: PLoS Pathogens, Vol. 2, No. 7, 07.2006.

Research output: Contribution to journalArticle

Parsa, KVL, Ganesan, LP, Rajaram, MVS, Gavrilin, MA, Balagopal, A, Mohapatra, NP, Wewers, MD, Schlesinger, LS, Gunn, JS & Tridandapani, S 2006, 'Macrophage pro-inflammatory response to Francisella novicida infection is regulated by SHIP.', PLoS Pathogens, vol. 2, no. 7. https://doi.org/10.1371/journal.ppat.0020071
Parsa, Kishore V.L. ; Ganesan, Latha P. ; Rajaram, Murugesan V.S. ; Gavrilin, Mikhail A. ; Balagopal, Ashwin ; Mohapatra, Nrusingh P. ; Wewers, Mark D. ; Schlesinger, Larry S. ; Gunn, John S. ; Tridandapani, Susheela. / Macrophage pro-inflammatory response to Francisella novicida infection is regulated by SHIP. In: PLoS Pathogens. 2006 ; Vol. 2, No. 7.
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abstract = "Francisella tularensis, a Gram-negative facultative intracellular pathogen infecting principally macrophages and monocytes, is the etiological agent of tularemia. Macrophage responses to F. tularensis infection include the production of pro-inflammatory cytokines such as interleukin (IL)-12, which is critical for immunity against infection. Molecular mechanisms regulating production of these inflammatory mediators are poorly understood. Herein we report that the SH2 domain-containing inositol phosphatase (SHIP) is phosphorylated upon infection of primary murine macrophages with the genetically related F. novicida, and negatively regulates F. novicida-induced cytokine production. Analyses of the molecular details revealed that in addition to activating the MAP kinases, F. novicida infection also activated the phosphatidylinositol 3-kinase (PI3K)/Akt pathway in these cells. Interestingly, SHIP-deficient macrophages displayed enhanced Akt activation upon F. novicida infection, suggesting elevated PI3K-dependent activation pathways in absence of SHIP. Inhibition of PI3K/Akt resulted in suppression of F. novicida-induced cytokine production through the inhibition of NFkappaB. Consistently, macrophages lacking SHIP displayed enhanced NFkappaB-driven gene transcription, whereas overexpression of SHIP led to decreased NFkappaB activation. Thus, we propose that SHIP negatively regulates F. novicida-induced inflammatory cytokine response by antagonizing the PI3K/Akt pathway and suppressing NFkappaB-mediated gene transcription. A detailed analysis of phosphoinositide signaling may provide valuable clues for better understanding the pathogenesis of tularemia.",
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AU - Gavrilin, Mikhail A.

AU - Balagopal, Ashwin

AU - Mohapatra, Nrusingh P.

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