Top

Inflammopharmacology

Published in:

01-04-2018 | Original Article

Caffeic acid combined with autoclaved Leishmania major boosted the protection of infected BALB/c mice by enhancing IgG2 production, IFN-γ/TGF-β and iNO synthase/arginase1 ratios, and the death of infected phagocytes

Authors: Radia Belkhelfa-Slimani, Bahia Djerdjouri

Published in: Inflammopharmacology | Issue 2/2018

Abstract

Background

Immunization with killed Leishmania promastigotes without adjuvant was considered as safe, but gave variable rates of protection. Taking advantage of the immuno-modulatory effect of caffeic acid (CA), a natural polyphenolic antioxidant, we investigated its potentiating effect in autoclaved Leishmania major (ALM)-induced protection of Leishmania major-infected BALB/c.

Methods

First, BALB/c mice were sensitized for 6 weeks either with CA, or ALM alone or combined with caffeic acid (ALM–CA) or Freund’s adjuvant (ALM–FA), and subsequently infected with L. major promastigotes. Second, to test the curative effect, CA was given daily for 5 weeks to susceptible mice, starting on week 4 post-infection. Sera, footpads and lymph nodes (LNs) were collected at week 9 post-infection and submitted to biochemical or histological analyses.

Results

Compared to the respective controls, our results showed that CA directly healed footpad lesions and reduced the hallmarks of cutaneous leishmaniasis including oxidative inflammation, parasite load, and phagocytes influx and infestation. In sensitized mice, the protection enhanced gradually from ALM–FA, CA, ALM to ALM–CA in parallel to decreased seric IgGt levels. In contrast to ALM–FA, the combined effect of ALM and CA increased specific isotype IgG2, and decreased IL-17 and MCP-1, and phagocyte influx, as attested by the concomitant reduction in myeloperoxidase (MPO) and α-naphthyl acetate esterase (ANAE) activities. ALM–CA shifted IFN-γ/TGF-β and iNO synthase/arginase1 (iNOS/Arg1) balances in a Th1 immune response that control efficiently cutaneous lesions and LNs hypertrophy, and reactivate the death of infected phagocytes.

Conclusions

Therefore, CA combined with ALM synergizes with L. major antigens for priming innate cells, through early polarization to optimal Th1 response that leads to IFN-γ and iNOS-dependent leishmanicidal activity of neutrophils and macrophages.

Graphical Abstract

Abi Abdallah DS, Denkers ET (2012) Neutrophils cast extracellular traps in response to protozoan parasites. Front Immunol 3:1–6

Bahar K, Dowlati LY, Shidani B, Alimohammadian MH, Khamesipour A, Ehsasi S et al (1996) Comparative safety and immunogenicity trial of two killed Leishmania major vaccines with or without BCG in human volunteers. Clin Dermatol 14(5):489–495CrossRefPubMed

Belazzoug S (1985) A new enzymatic variant of Leishmania infantum Nicolle, 1908, agent of cutaneous leishmaniasis in northern Algeria. Ann Parasitol Hum Comp 60(1):1–3CrossRefPubMed

Belkhelfa-Slimani R, Djerdjouri B (2017) Caffeic acid and quercetin exert caspases-independent apoptotic effects on Leishmania major promastigotes, and reactivate the death of infected phagocytes derived from BALB/c mice. Asian Pac J Trop Biomed 7(4):321–331CrossRef

Bradford MM (1976) A rapid and sensitive method for the quantitation of microgram quantities of protein utilizing the principle of protein-dye binding. Anal Biochem 72:248–254CrossRefPubMed

Brunner R, Jensen-Jarolim E, Pali-Schöll I (2010) The ABC of clinical and experimental adjuvants—a brief overview. Immunol Lett 128(1):29–35CrossRefPubMed

Buffet PA, Sulahian A, Garin YJ, Nassar N, Derouin F (1995) Culture microtitration: a sensitive method for quantifying Leishmania infantum in tissues of infected mice. Antimicrob Agents Chemother 39(9):2167–2168CrossRefPubMedPubMedCentral

Conrad SM, Strauss-Ayali D, Field AE, Mack M, Mosser DM (2007) Leishmania-derived murine monocyte chemoattractant protein 1 enhances the recruitment of a restrictive population of CC Chemokine receptor 2-positive macrophages. Infect Immun 75(2):653–665CrossRefPubMed

Corraliza IM, Soler G, Eichmann K, Modolell M (1995) Arginase induction by suppressors of nitric oxide synthesis (IL-4, IL-10 and PGE2) in murine bone marrow-derived macrophages. Biochem Biophys Res Commun 206:667–673CrossRefPubMed

Darrah PA, Patel DT, De Luca PM, Lindsay RW, Davey DF, Flynn BJ et al (2007) Multifunctional TH1 cells define a correlate of vaccine-mediated protection against Leishmania major. Nat Med 13:843–850CrossRefPubMed

De Luca PM, Barreto Macedo AB (2016) Cutaneous leishmaniasis vaccination: a matter of quality. Front Immun 7:151

Desjeux P (2004) Leishmaniasis: current situation and new perspectives. Comp Immunol Microb Infect Dis 27:305–318CrossRef

Ding AH, Nathan CF, Stuehr DJ (1988) Release of reactive nitrogen intermediates and reactive oxygen intermediates from mouse peritoneal macrophages: comparison of activating cytokines and evidence for independent production. J Immunol 141:2407–2412PubMed

Gantt KR, Schultz-Cherry S, Rodriguez N, Jeronimo SMB, Nascimento ET, Goldman TL et al (2003) Activation of TGF-β by Leishmania chagasi: importance for parasite survival in macrophages. J Immunol 170(5):2613–2620CrossRefPubMed

Gonzalez-Lombana C, Gimblet C, Bacellar O, Oliveira WW, Passos S et al (2013) IL-17 mediates immunopathology in the absence of IL-10 following Leishmania major infection. PLoS Pathog 9(3):e1003243CrossRefPubMedPubMedCentral

Gutiérrez-Kobeh L, de Oyarzabal E, Argueta J, Wilkins A, Salaiza N, Fernandez E et al (2013) Inhibition of dendritic cell apoptosis by Leishmania mexicana amastigotes. Parasitol Res 112(4):1755–1762CrossRefPubMed

Hadmman E (2001) Leishmaniasis: current status of vaccine development. Clin Microb Rev 14(2):229–243CrossRef

Harrat Z, Boubidi SC, Pratlong F, Benikhlef R, Selt B, Dedet JP et al (2009) Description of a dermatropic Leishmania close to L. killicki (Rioux, Lanotte & Pratlong 1986) in Algeria. Trans R Soc Trop Med Hyg 103:16–20CrossRef

Hurrell BP, Schuster S, Grün E, Coutaz M, Williams RA, Held W et al (2015) Rapid sequestration of Leishmania mexicana by neutrophils contributes to the development of chronic lesion. PLoS Pathog 11(5):e1004929CrossRefPubMedPubMedCentral

Iniesta V, Carcelen J, Molano I, Peixoto PMV, Redondo E, Parra P, Mangas M et al (2005) Arginase I induction during Leishmania major infection mediates the development of disease. Infect Immun 73(9):6085–6090CrossRefPubMedPubMedCentral

Jochim RC, Teixeira C (2009) Leishmania commandeers the host inflammatory response through neutrophils. Trends Parasitol 25(4):145–147CrossRefPubMed

Katara GK, Ansari NA, Singh A, Ramesh V, Salotra P (2012) Evidence for involvement of Th17 type responses in post Kala Azar dermal Leishmaniasis (PKDL). PLoS Negl Trop Dis 6(6):e1703CrossRefPubMedPubMedCentral

Khamesipour A, Rafati S, Davoudi N, Maboudi F, Modabber F (2006) Leishmaniasis vaccine candidates for development: a global overview. Ind J Med Res 123:423–438

Krawisz JE, Sharon P, Stenson WF (1984) Quantitative assay for acute intestinal inflammation based on myeloperoxidase activity. Assessment of inflammation in rat and hamster models. Gastroenterology 87(6):1344–1350PubMed

Kumar R, Bumb RA, Salotra P (2009) Evaluation of localized and systemic immune responses in cutaneous leishmaniasis caused by Leishmania tropica: interleukin-8, monocyte chemotactic protein-1 and nitric oxide are major regulatory factors. Immunology 130:193–201CrossRef

Lagranderie MRR, Balazuc AM, Deriaud E, Leclerc CD, Gheorghiu M (1996) Comparison of immune responses of mice immunized with five different Mycobacterium bovis BCG vaccine strains. Infect Immun 64(1):1–9PubMedPubMedCentral

Laskay T, van Zandbergen G, Solbach W (2008) Neutrophil granulocytes as host cells and transport vehicles for intracellular pathogens: apoptosis as infection-promoting factor. Immunobiology 213:183–191CrossRefPubMed

Li J, Hunter CA, Farrell JP (1999) Anti-TGF-β treatment promotes rapid healing of Leishmania major infection in mice by enhancing in vivo nitric oxide production. J Immunol 162:974–979PubMed

Lopes MF, Costa-da-Silva AC, DosReis GA (2014) Innate immunity to Leishmania infection: within phagocytes. Mediat Inflam 2014:754965CrossRef

Lopez Kostka S, Dinges S, Griewank K, Iwakura Y, Udey MC, von Stebut E (2009) IL-17 promotes progression of cutaneous leishmaniasis in susceptible mice. J Immunol 182:3039–3046CrossRefPubMed

Mukherjee P, Sen PC, Ghose AC (2006) Lymph node cells from BALB/c mice with chronic visceral leishmaniasis exhibiting cellular anergy and apoptosis: involvement of Ser/Thr phosphatase. Apoptosis 11(11):2013–2029CrossRefPubMed

Mutiso JM, Macharia JC, Mutisya RM, Taracha E (2010) Subcutaneous immunization against Leishmania major-infection in mice: efficacy of formalin-killed promastigotes combined with adjuvants. Rev Inst Med Trop Sao Paulo 52(2):95–100CrossRefPubMed

Ng LG, Hsu A, Mandell MA, Roediger B, Hoeller C, Mrass P et al (2008) Migratory dermal dendritic cells act as rapid sensors of protozoan parasites. PLoS Pathog 4:e1000222CrossRefPubMedPubMedCentral

Okwor I, Mou Z, Liu D, Uzonna J (2012) Protective immunity and vaccination against cutaneous Leishmaniasis. Front Immunol 3:1–13CrossRef

Paiva CN, Feijo DF, Dutra FF, Carneiro VC, Freitas GB, Alves LS et al (2012) Oxidative stress fuels Trypanosoma cruzi infection in mice. J Clin Invest 122(7):2531–2542CrossRefPubMedPubMedCentral

Parody N, Soto M, Requena JM, Alonso C (2004) Adjuvant guided polarization of the immune humoral response against a protective multicomponent antigenic protein (Q) from Leishmania infantum. A CpG + Q mix protects BALB/c mice from infection. Parasite Immunol 26:283–293CrossRefPubMed

Pereira L, Abbehusen M, Teixeira C, Cunha J, Nascimento IP, Fukutani K et al (2015) Vaccination with Leishmania infantum acidic ribosomal P0 but not with nucleosomal histones proteins controls Leishmania infantum infection in hamsters. PLoS Negl Trop Dis 9(2):e0003490CrossRefPubMedPubMedCentral

Peters NC, Sacks D (2009) The impact of vector mediated neutrophil recruitment on cutaneous Leishmaniasis. Cell Microbiol 11(9):1290–1296CrossRefPubMedPubMedCentral

Peters NC, Egen JG, Secundino N, Debrabant A, Kimblin N, Kamhawi S et al (2008) In vivo imaging reveals an essential role for neutrophils in Leishmaniasis transmitted by sand flies. Science 321(5891):970–974CrossRefPubMedPubMedCentral

Peters NC, Bertholet S, Lawyer PG, Charmoy M, Romano A, Ribeiro-Gomes FL et al (2012) Evaluation of recombinant Leishmania polyprotein plus glucopyranosyl lipid a stable emulsion vaccines against sand fly-transmitted Leishmania major in C57BL/6 Mice. J Immunol 189:4832–4841CrossRefPubMedPubMedCentral

Pinheiro RO, Pinto EF, Lopes JRC, Guedes HLM, Fentanes RF, Rossi-Bergmann B (2005) TGF-β-associated enhanced susceptibility to leishmaniasis following intramuscular vaccination of mice with Leishmania amazonensis antigens. Microbes Infect 7(13):1317–1323CrossRefPubMed

Radtke OA, Foo LY, Lu Y, Kiderlen AF, Kolodziej H (2003) Evaluation of sage phenolics for their antileishmanial activity and modulatory effects on interleukin-6, interferon and tumour necrosis factor-alpha-release in RAW 264.7 cells. Z Naturforschung C58(5–6):395–400

Ribeiro-Gomes FL, Peters NC, Debrabant A, Sacks DL (2012) Efficient capture of infected neutrophils by dendritic cells in the skin inhibits the early anti-Leishmania response. PLoS Pathog 8(2):e1002536CrossRefPubMedPubMedCentral

Ribeiro-Gomes FL, Romano A, Lee S, Roffê E, Peters NC, Debrabant A, Sacks D (2015) Apoptotic cell clearance of Leishmania major-infected neutrophils by dendritic cells inhibits CD8+ T-cell priming in vitro by Mer tyrosine kinase-dependent signaling. Cell Death Dis 6:e2018CrossRefPubMedPubMedCentral

Rosa R, Marques C, Rodrigues OR, Santos-Gomes GM (2007) Immunization with Leishmania infantum released proteins confers partial protection against parasite infection with a predominant Th1 specific immune response. Vaccine 25:4525–4532CrossRefPubMed

Sacks D, Anderson C (2004) Re-examination of the immunosuppressive mechanisms mediating non-cure of Leishmania infection in mice. Immunol Rev 201(1):225–238CrossRefPubMed

Sarkar A, Aga E, Bussmeyer U, Bhattacharyya A, Möller S, Hellberg L et al (2013) Infection of neutrophil granulocytes with Leishmania major activates ERK 1/2 and modulates multiple apoptotic pathways to inhibit apoptosis. Med Microbiol Immunol 202:25–35CrossRefPubMed

Scott P (2005) Micro review: immunologic memory in cutaneous Leishmaniasis. Cell Microb 12:1707–1713CrossRef

Soares-Silva M, Diniz F, Gomes GN, Diana B (2016) The mitogen activated protein kinase (MAPK) pathway: role in immune evasion by trypanosomatids. Front Microb doi: 10.3389/fmicb.2016.00183

Tounsi N, Meghari S, Moser M, Djerdjouri B (2015) Lysophosphatidylcholine exacerbates Leishmania major-dendritic cell infection through interleukin-10 and a burst in arginase1 and indoleamine 2,3-dioxygenase activities. Int Immunopharmacol 25(1):1–9CrossRefPubMed

Van Zandbergen G, Klinger M, Mueller A, Dannenberg S, Gebert A, Solbach W, Laskay T (2004) Cutting edge: neutrophil granulocyte serves as a vector for Leishmania entry into macrophages. J Immunol. 173(11):6521–6525CrossRefPubMed

Wahl SM, Swisher J, McCartney-Francis N, Chen W (2004) TGF-β: the perpetrator of immune suppression by regulatory T cells and suicidal T cells. J Leukoc Biol 76:15–24CrossRefPubMed

Zhang WW, Matlashewski G (2008) Immunization with a toll-like receptor 7 and/or 8 agonist vaccine adjuvant increases protective immunity against Leishmania major in BALB/c Mice. Infect Immun 76(8):3777–3783CrossRefPubMedPubMedCentral

Zhou X, Scharf ME, Meinke LJ, Chandler LD, Siegfried BD (2003) Characterization of general esterases from methyl parathion-resistant and -susceptible populations of western corn rootworm (Coleoptera: Chrysomelidae). J Econ Entomol 96(6):1855–1863CrossRefPubMed

Title: Caffeic acid combined with autoclaved Leishmania major boosted the protection of infected BALB/c mice by enhancing IgG2 production, IFN-γ/TGF-β and iNO synthase/arginase1 ratios, and the death of infected phagocytes
Authors: Radia Belkhelfa-Slimani
Bahia Djerdjouri
Publication date: 01-04-2018
Publisher: Springer International Publishing
Published in: Inflammopharmacology / Issue 2/2018
Print ISSN: 0925-4692
Electronic ISSN: 1568-5608
DOI: https://doi.org/10.1007/s10787-017-0399-z

At a glance: The STEP trials

Springer Medicine

Caffeic acid combined with autoclaved Leishmania major boosted the protection of infected BALB/c mice by enhancing IgG2 production, IFN-γ/TGF-β and iNO synthase/arginase1 ratios, and the death of infected phagocytes

Abstract

Background

Methods

Results

Conclusions

Graphical Abstract

At a glance: The STEP trials

Springer Medicine

Abstract

Background

Methods

Results

Conclusions

Graphical Abstract

Please log in to get access to this content

Other articles of this Issue 2/2018

The impact of mangiferin from Belamcanda chinensis on experimental colitis in rats

Inhibitory effects of andrographolide on activated macrophages and adjuvant-induced arthritis

Teniposide ameliorates bone cancer nociception in rats via the P2X7 receptor

Arctium minus crude extract presents antinociceptive effect in a mice acute gout attack model

Diligustilide releases H2S and stabilizes S-nitrosothiols in ethanol-induced lesions on rat gastric mucosa

Anti-inflammatory evaluation and characterization of leaf extract of Ananas comosus