Toll-like receptors and CD40 modulate each other's expression affecting <i>Leishmania major</i> infection

Chandel, Himanshu Singh; Pandey, Surya Prakash; Shukla, Divanshu; Lalsare, K.M.; Selvaraj, Sathishkumar; Jha, Mukesh Kumar; Saha, Bhaskar

doi:10.1111/cei.12264

Cited by 25 publications

(30 citation statements)

References 35 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Neutrophil granule enzymes, such as NE, could activate the microbicidal functions of macrophages through interactions with surface receptors (49). TLR2 and TLR4 could be trigged by proteolytically active NE on infected macrophages, leading to an oxidative response, TNF-a production, and parasite killing (26,(50)(51)(52). Our data indicate that each en-FIGURE 7.…”

Section: Discussionmentioning

confidence: 89%

Degranulating Neutrophils Promote Leukotriene B4 Production by Infected Macrophages To Kill Leishmania amazonensis Parasites

Tavares

Afonso

Suarez

et al. 2016

The Journal of Immunology

View full text Add to dashboard Cite

Neutrophils mediate early responses against pathogens, and they become activated during endothelial transmigration toward the inflammatory site. In the current study, human neutrophils were activated in vitro with immobilized extracellular matrix proteins, such as fibronectin (FN), collagen, and laminin. Neutrophil activation by FN, but not other extracellular matrix proteins, induces the release of the granules’ contents, measured as matrix metalloproteinase 9 and neutrophil elastase activity in culture supernatant, as well as reactive oxygen species production. Upon contact with Leishmania amazonensis–infected macrophages, these FN-activated neutrophils reduce the parasite burden through a mechanism independent of cell contact. The release of granule proteases, such as myeloperoxidase, neutrophil elastase, and matrix metalloproteinase 9, activates macrophages through TLRs, leading to the production of inflammatory mediators, TNF-α and leukotriene B4 (LTB4), which are involved in parasite killing by infected macrophages. The pharmacological inhibition of degranulation reverted this effect, abolishing LTB4 and TNF production. Together, these results suggest that FN-driven degranulation of neutrophils induces the production of LTB4 and TNF by infected macrophages, leading to the control of Leishmania infection.

show abstract

Section: Discussionmentioning

confidence: 89%

Degranulating Neutrophils Promote Leukotriene B4 Production by Infected Macrophages To Kill Leishmania amazonensis Parasites

Tavares

Afonso

Suarez

et al. 2016

The Journal of Immunology

View full text Add to dashboard Cite

show abstract

“…In our preceding report, we showed that astrakurkurone could inhibit the intracellular amastigotes, the pathogenic stage in mammalian host, by inducing ROS in macrophages, with a 50% inhibitory concentration of 2.5 g/ml in vitro (16). Interestingly, astrakurkurone also induced the generation of NO, an essential antiamastigote effector molecule (21,26,(28)(29)(30)(31)(32), considerably in uninfected macrophages and significantly in infected macrophages. The induction of inflammatory response was further reflected by an induction of a proinflammatory cytokine, IL-12, and a fall of the anti-inflammatory cytokines IL-10 and TGF-␤ by astrakurkurone.…”

Section: Discussionmentioning

confidence: 90%

“…It preserves the benefit of this molecule as antileishmanial therapy, because endogenous TNF-␣ has been reported to induce apoptosis in host macrophages (43). A significant surge in the nitric oxide level in infected macrophages can be justified due to the engagement of CD40 (21) and TLR9 (30) or ultimately because of the activation of NF-B by astrakurkurone. It has been well documented that all TLRs can enhance CD40 expression, while CD40 augments the expression of only TLR9 (30).…”

Section: Discussionmentioning

confidence: 99%

“…A significant surge in the nitric oxide level in infected macrophages can be justified due to the engagement of CD40 (21) and TLR9 (30) or ultimately because of the activation of NF-B by astrakurkurone. It has been well documented that all TLRs can enhance CD40 expression, while CD40 augments the expression of only TLR9 (30). As both CD40 and TLR9 can induce expression of IL-12, a cytokine that promotes the IFN-␥-secreting Th1-cell differentiation, the CD40-TLR9 crossregulation implies a positive role in Leishmania infection (31).…”

Section: Discussionmentioning

confidence: 99%

“…4). As CD40, IL-12, and TLRs modulate each other in initiation of cellular activation leading to parasite clearance (30)(31)(32)(33)(34)(35)(36)(37)(38)(39)(40), we next attempted to explore the involvement of TLRs in astrakurkurone-mediated immunomodulation (Fig. 4).…”

Section: Astrakurkurone-induced Nitric Oxide Caused the Inhibition Ofmentioning

confidence: 99%

See 2 more Smart Citations

Successful Therapy of Murine Visceral Leishmaniasis with Astrakurkurone, a Triterpene Isolated from the Mushroom Astraeus hygrometricus, Involves the Induction of Protective Cell-Mediated Immunity and TLR9

Mallick

Dutta

Chaudhuri

et al. 2016

Antimicrob Agents Chemother

View full text Add to dashboard Cite

eIn our previous report, we showed that astrakurkurone, a triterpene isolated from the Indian mushroom Astraeus hygrometricus (Pers.) Morgan, induced reactive oxygen species, leading to apoptosis in Leishmania donovani promastigotes, and also was effective in inhibiting intracellular amastigotes at the 50% inhibitory concentration of 2.5 g/ml. The aim of the present study is to characterize the associated immunomodulatory potentials and cellular activation provided by astrakurkurone, leading to effective antileishmanial activity in vitro and in vivo. Astrakurkurone-mediated antileishmanial activity was evaluated by real-time PCR and flow cytometry. The involvement of Toll-like receptor 9 (TLR9) was studied by in vitro assay in the presence of a TLR9 agonist and antagonist and by in silico modeling of a three-dimensional structure of the ectodomain of TLR9 and its interaction with astrakurkurone. Astrakurkurone caused a significant increase in TLR9 expression of L. donovani-infected macrophages along with the activation of proinflammatory responses. The involvement of TLR9 in astrakurkurone-mediated amastigote killing has been evidenced from the fact that a TLR9 agonist (CpG, ODN 1826) in combination with astrakurkurone enhanced the amastigote killing, while a TLR9 antagonist (bafilomycin A1) alone or in combination with astrakurkurone curbed the amastigote killing, which could be further justified by in silico evidence of docking between mouse TLR9 and astrakurkurone. Astrakurkurone was found to reduce the parasite burden in vivo by inducing protective cytokines, gamma interferon and interleukin 17. Moreover, astrakurkurone was nontoxic toward peripheral blood mononuclear cells of immunocompromised patients with visceral leishmaniasis. Astrakurkurone, a nontoxic antileishmanial, enhances the immune efficiency of host cells, leading to parasite clearance in vitro and in vivo.

show abstract

March of Mycobacterium: miRNAs intercept host cell CD40 signalling

Chauhan

Dandapat

Sarkar³

et al. 2020

Clin & Trans Imm

View full text Add to dashboard Cite

The disease tuberculosis is fatal if untreated. It is caused by the acid-fast bacilli Mycobacterium tuberculosis. Mycobacterium resides and replicates within the alveolar macrophages, causing inflammation and granuloma, wherein macrophage-T cell interactions enhance the inflammation-causing pulmonary caseous lesions. The first interactions between Mycobacterium and the receptors on macrophages decide the fate of Mycobacterium because of phagolysosomal impairments and the expression of several miRNAs, which may regulate CD40 expression on macrophages. While the altered phagolysosomal functions impede antigen presentation to the T cell-expressed antigen receptor, the interactions between the macrophage-expressed CD40 and the T cell-expressed CD40-ligand (CD40L or CD154) provide signals to T cells and Mycobacterium-infected macrophages. These two functions significantly influence the resolution or persistence of Mycobacterium infection. CD40 controls T-cell polarisation and host-protective immunity by eliciting interleukin-12p40, nitric oxide, reactive oxygen species and IFN-c production. Indeed, CD40deficient mice succumb to low-dose aerosol infection with Mycobacterium because of deficient interleukin (IL)-12 production leading to impaired IFN-c-secreting T-cell response. In contrast, despite generating fewer granulomas, the CD40L-deficient mice developed anti-mycobacterial T-cell responses to the levels observed in the wild-type mice. These host-protective responses are significantly subdued by the Mycobacterium-infected macrophage produced TGF-b and IL-10, which promote promycobacterial T-cell responses. The CD40-CD40L-induced counteractive immune responses against Mycobacterium thus present a conundrum that we explain here with a reconciliatory hypothesis. Experimental validation of the hypothesis will provide a rationale for designing anti-tubercular immunotherapy.

show abstract

Toll-like receptors and CD40 modulate each other's expression affecting Leishmania major infection

Cited by 25 publications

References 35 publications

Degranulating Neutrophils Promote Leukotriene B4 Production by Infected Macrophages To Kill Leishmania amazonensis Parasites

Degranulating Neutrophils Promote Leukotriene B4 Production by Infected Macrophages To Kill Leishmania amazonensis Parasites

Successful Therapy of Murine Visceral Leishmaniasis with Astrakurkurone, a Triterpene Isolated from the Mushroom Astraeus hygrometricus, Involves the Induction of Protective Cell-Mediated Immunity and TLR9

March of Mycobacterium: miRNAs intercept host cell CD40 signalling

Contact Info

Product

Resources

About