Oceanimonas sp. BPMS22-derived protein protease inhibitor induces anti-leishmanial immune responses through macrophage M2 to M1 repolarization

Jayaraman, Adithyan; Srinivasan, Sujatha; Kar, Amrita Ghosh; Harish, B.S.; Raja, Mamilla R. Charan; Uppuluri, Kiran Babu; Mahapatra, Santanu Kar

doi:10.1016/j.intimp.2022.109281

Cited by 4 publications

(5 citation statements)

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“…Previous experiments found that the BPMS22-derived PPI modulated the M1–M2 markers and shifted the macrophage towards the M1 phenotype ( Jayaraman et al., 2022 ). Moreover, we have also found that the PPI modulated TLR4 in uninfected and infected macrophages over the other TLRs.…”

Section: Resultsmentioning

confidence: 94%

“…The report indicated that activation of TLR-2, TLR-4, TLR-6, and TLR-9 could exert an anti-leishmanial immune response by the surge of pro-inflammatory cytokines and iNOS2-mediated nitrite generation ( Bhattacharya et al., 2010 ; Mukherjee et al., 2012 ; Pandey et al., 2014 ). PPI-induced iNOS2 mRNA expression and nitrite release in macrophages ( Jayaraman et al., 2022 ) and enhanced the TLR-4 expression. We may consider the possibility of TLR4 as the target of the PPI to induce the anti-VL immune response.…”

Section: Resultsmentioning

confidence: 99%

“…of BPMS22–PPI. The in vivo dose was selected, as reported earlier ( Jayaraman et al., 2022 ). After 15 days, the mice were sacrificed, and the livers and spleens were analyzed to confirm the stability of TLR-4 knockdown in the TLR-4 shRNA-treated group.…”

Section: Resultsmentioning

confidence: 99%

“…In a previous study, BPMS22–PPI was well-proven to shift macrophages toward the pro-inflammation state in the pre-stimulated macrophage and leishmanial infection model ( Jayaraman et al., 2022 ). The expression of iNOS-mediated nitric oxide aids in lowering parasite load in in vitro and in vivo conditions.…”

Section: Discussionmentioning

confidence: 96%

“…that showed better IC 50 of 25.28 ± 1.675 and 0.415 ± 0.015 μg/ml against both promastigote and amastigote, respectively. The PPI exhibited potent immune modulation shifting from anti-inflammatory to the increased pro-inflammatory status of macrophages (M2–M1) in the pre-stimulated macrophages and Leishmania infection model ( Jayaraman et al., 2022 ). In the current study, we have unraveled the underlying mechanism behind the PPI-mediated repolarization of M2–M1 macrophages with the help of TLR-4 siRNA/shRNA.…”

Section: Introductionmentioning

confidence: 99%

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Unwinding the mechanism of macrophage repolarization potential of Oceanimonas sp. BPMS22-derived protein protease inhibitor through Toll-like receptor 4 against experimental visceral leishmaniasis

Jayaraman

Srinivasan

Uppuluri

et al. 2023

Front. Cell. Infect. Microbiol.

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The Oceanimonas sp. BPMS22-derived protein protease inhibitor (PPI) has been proven to shift macrophages towards an inflammatory state and reduce Leishmania donovani infection in vitro and in vivo. The current study explored and validated the mechanistic aspects of the PPI and Toll-like receptor (TLR) interaction. The PPI exhibited the upregulation of TLR2, TLR4, and TLR6 during treatment which was proven to orchestrate parasite clearance effectively. An in silico study confirmed the high interaction with TLR4 and PPI. Immune blotting confirmed the significant upregulation of TLR4 in macrophages irrespective of L. donovani infection. Pharmacological inhibition and immune blot study confirmed the involvement of the PPI in TLR4-mediated phosphorylation of p38 MAPK and dephosphorylation of ERK1/2, repolarizing to pro-inflammatory macrophage state against experimental visceral leishmaniasis. In addition, in TLR4 knockdown condition, PPI treatment failed to diminish M2 phenotypical markers (CD68, Fizz1, Ym1, CD206, and MSR-2) and anti-inflammatory cytokines (IL-4, IL-10, and TGF-β). Simultaneously, the PPI failed to upregulate the M1 phenotypical markers and pro-inflammatory cytokines (IL-1β, IL-6, IL-12, and IFN-γ) (p < 0.001) during the TLR4 knockdown condition. In the absence of TLR4, the PPI also failed to reduce the parasite load and T-cell proliferation and impaired the delayed-type hypersensitivity response. The absence of pro-inflammatory cytokines was observed during a co-culture study with PPI-treated macrophages (in the TLR4 knockdown condition) with day 10 T-cell obtained from L. donovani-infected mice. This study supports the immunotherapeutic potential of the PPI as it interacted with TLR4 and promoted macrophage repolarization (M2–M1) to restrict the L. donovani parasite burden and helps in the mounting immune response against experimental visceral leishmaniasis.

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Section: Resultsmentioning

confidence: 94%