Cited by 47Heme Oxygenase-1 and Carbon MonoxideResearch on Leishmaniasis StudiesLeprosy Research and Treatment

Leishmania donovani Exploits Macrophage Heme Oxygenase-1 To Neutralize Oxidative Burst and TLR Signaling–Dependent Host Defense

Saha, Shriya, Basu, Moumita, Guin, Subham, Gupta, Purnima, Mitterstiller, Anna-Maria, Weiss, Guenter, Jana, Kuladip, Ukil, Anindita·2019·The Journal of Immunology

Abstract

Screening of macrophage antioxidant enzymes during infection revealed marked upregulation of the heme-degrading enzyme, heme oxygenase-1 (HO-1). Moreover, HO-1-silenced RAW macrophages depicted increased superoxide production and decreased parasite survival. HO-1 induction decreased cellular heme content, thereby inhibiting the heme-dependent maturation of gp91phox, a catalytic component of major reactive oxygen species-producing enzyme NAD(P)H oxidase. Decreased gp91phox expression resulted in reduced stability of p22phox, another component of the catalytic center of NAD(P)H oxidase. Replenishing infected cells with exogenous heme reversed these effects and restored NAD(P)H oxidase activity. Persistent HO-1 expression at late hour of infection prompted us to investigate its effect on other host defense parameters, and inhibition study revealed a reciprocal relationship of HO-1 with host proinflammatory responses. Among all the HO-1-mediated heme degradation products (CO, Fe, and biliverdin), only CO documented potent anti-inflammatory effects. Quenching of CO during infection increased the production of disease-resolving cytokines IL-12 and TNF-α. Coimmunoprecipitation experiments revealed that CO inhibited the interaction of TLR4 with MyD88 and TIR domain-containing adapter-inducing IFN-β, thereby dampening the activation of NF-κB and IFN regulatory factor 3-mediated production of proinflammatory cytokines. Administration of HO-1 inhibitor tin protoporphyrin IX dichloride in infected BALB/c mice led to a decrease in liver and spleen parasite burden along with increased production of IL-12 and TNF-α. These results suggest that HO-1 on one hand inhibits reactive oxygen species generation and on the other hand downregulates host favorable cytokine responses, thereby facilitating intramacrophage parasite survival.

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Crossref · 10.4049/jimmunol.1800958

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  • Leishmania induces HO1 for acquisition of molecular iron and for protection from host-mediated formation of antimicrobial radicals.

    “In addition, Leishmania induces HO1 for acquisition of molecular iron and for protection from host-mediated formation of antimicrobial radicals (Saha et al., 2019).”

    From Iron in infection and immunity (2020) · cites this paper as Saha et al., 2019

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Authors
Saha, S., Basu, M., Guin, S., Gupta, P., Mitterstiller, A.-M., Weiss, G., Jana, K., & Ukil, A.
Affiliations
  • University of Calcutta (IN)
  • Jadavpur University (IN)
  • Centre international de recherche sur le cancer (FR)
  • Innsbruck Medical University (AT)
  • Department of Internal Medicine II, Infectious Diseases, Immunology, Rheumatology, Pneumology, Medical University of Innsbruck , 69008 Innsbruck ,
  • Bose Institute (IN)
Corresponding author
  • Saha, Shriya
  • Basu, Moumita
  • Ukil, Anindita
Venue
The Journal of Immunology
Published
2019-02-01
Volume
202
Issue
3
Pages
827-840
ISSN
  • 0022-1767 (ISSN-L)
  • 1550-6606
OpenAlex
W2907823975
Cited by
47
References
55
Citations by year
2026: 4 · 2025: 4 · 2024: 6 · 2023: 6 · 2022: 7 · 2021: 7 · 2020: 8 · 2019: 5
FWCI
1.78
Type
journal article
Language
en
Open access
closed
Locations
  • The Journal of Immunology (publishedVersion)
  • PubMed (publishedVersion)
Funders
  • World Health Organization
  • Division of Graduate Education
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Heme Oxygenase-1 and Carbon Monoxide
  • Health Sciences › Medicine › Public Health, Environmental and Occupational Health › Research on Leishmaniasis Studies
  • Health Sciences › Medicine › Infectious Diseases › Leprosy Research and Treatment
Keywords
Leishmania donovani, heme oxygenase-1, macrophages, respiratory burst, NADPH oxidase, gp91phox, p22phox, heme degradation, carbon monoxide, TLR4 signaling, MyD88, TIRAP, NF-κB, IL-12, TNF-α, tin protoporphyrin IX, parasite survival, host-parasite interactions, anti-inflammatory response
MeSH terms
RAW 264.7 Cells, NADPH Oxidase 2, Animals, Female, Host-Parasite Interactions, Leishmania donovani, Macrophages, Membrane Proteins, Mice, Inbred BALB C, Protoporphyrins, Signal Transduction, Up-Regulation, Cytokines, Respiratory Burst, NADPH Oxidases, Toll-Like Receptor 4, Mice, Heme Oxygenase-1, Parasite Load

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