MAPK-directed phosphatases preferentially regulate pro- and anti-inflammatory cytokines in experimental visceral

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Deciphering the Molecular Mechanism and Function of Pore-Forming Toxins Using Leishmania major
08:17

Deciphering the Molecular Mechanism and Function of Pore-Forming Toxins Using Leishmania major

Published on: October 28, 2022

Susanta Kar1, Anindita Ukil, Gunjan Sharma

  • 1Infectious Diseases and Immunology Division, Indian Institute of Chemical Biology, Kolkata, India.

Journal of Leukocyte Biology
|March 5, 2010
PubMed

Insights

Leishmania donovani infection impairs macrophage function by altering MAPK signaling. Inhibiting specific phosphatases (MKP1, MKP3, PP2A) may restore immune responses and reduce parasite burden.

Area of Science:

  • Immunology
  • Molecular Biology
  • Parasitology

Background:

  • Leishmania donovani infection causes macrophage dysfunction via Mitogen-Activated Protein Kinase (MAPK) signaling impairment.
  • The precise role of phosphatases in this MAPK signaling disruption remains unclear.

Purpose of the Study:

  • To investigate the involvement of specific phosphatases (MKP1, MKP3, PP2A) in Leishmania-induced macrophage dysfunction.
  • To explore the therapeutic potential of inhibiting these phosphatases in Leishmania infection.

Main Methods:

  • Gene expression profiling to identify upregulated phosphatases in infected macrophages.
  • Pharmacological inhibition of phosphatases before Leishmania infection in vitro and in vivo (BALB/c mice).
  • Analysis of cytokine profiles (Th2 response, TNF-alpha, iNOS) and parasite burden.

Main Results:

  • Leishmania donovani infection upregulated MKP1, MKP3, and PP2A expression.
  • Inhibition of MKP1 favored a Th2 response by deactivating p38.
  • MKP3 and PP2A inhibition reduced iNOS expression via ERK1/2 deactivation.
  • Phosphatase inhibition in infected mice induced TNF-alpha and iNOS, reducing parasite burden.
  • PKC isoforms PKCzeta and PKCepsilon were linked to MKP3/PP2A and MKP1 induction, respectively.

Conclusions:

  • MAPK-directed phosphatases (MKP1, MKP3, PP2A) are implicated in the establishment of Leishmania infection.
  • Inhibiting these phosphatases may be a viable strategy for modulating immune responses and treating visceral leishmaniasis.

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