Sulforaphane reduces intracellular survival of Staphylococcus aureus in macrophages through inhibition of JNK and p38 MAPK‑induced inflammation

Deramaudt,Therese B.; Ali,Malika; Vinit,Stephane; Bonay,Marcel

doi:10.3892/ijmm.2020.4563

Sulforaphane reduces intracellular survival of Staphylococcus aureus in macrophages through inhibition of JNK and p38 MAPK‑induced inflammation

Authors:
- Therese B. Deramaudt
- Malika Ali
- Stephane Vinit
- Marcel Bonay
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Affiliations: Department of Neuromuscular Handicap: Biotherapies and Therapeutic Innovations, National Institute of Health and Medical Research, University of Versailles‑Saint‑Quentin‑en‑Yvelines, 78180 Montigny‑le‑Bretonneux, France
Published online on: April 1, 2020 https://doi.org/10.3892/ijmm.2020.4563
Pages: 1927-1941
Copyright: © Deramaudt et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

Macrophages are active contributors to the innate immune defense system. As macrophage activation is clearly affected by the surrounding microenvironment, the present study investigated the effect of sulforaphane (SFN) on the bactericidal activity of macrophages and the underlying molecular mechanisms involved in this process. Human THP‑1‑derived macrophages, primary human peripheral blood mononuclear cell‑derived macrophages, and primary mouse bone marrow derived‑macrophages (BMDMs) pretreated with SFN or DMSO were utilized in a model of Staphylococcus aureus infection. The results suggested that SFN pretreatment of macrophages effectively repressed the intracellular survival of S. aureus through modulation of p38/JNK signaling and decreased S. aureus‑induced caspases‑3/7‑dependent cell apoptosis, potentially through downregulation of microRNA (miR)‑142‑5p and miR‑146a‑5p. As SFN is a well‑known activator of nuclear factor erythroid 2‑related factor 2 (Nrf2), Nrf2‑/‑ BMDMs were used to demonstrate that the SFN‑mediated inhibitory effect was independent of Nrf2. Nevertheless, an increase in intracellular bacterial survival in Nrf2‑deficient macrophages was observed. In addition, SFN pretreatment suppressed S. aureus‑induced transcriptional expression of genes coding for the proinflammatory cytokines interleukin (IL)‑1β, IL‑6, and tumor necrosis factor‑α (TNF‑α), as well as for the M1 markers C‑C motif chemokine receptor 7, IL‑23 and inducible nitric oxide synthase (iNOS). Western blot analysis indicated that S. aureus challenge activated p38 mitogen‑activated protein kinase (MAPK) (p38) and c‑Jun N‑terminal kinase (JNK) MAPK signaling pathways, while SFN pretreatment prevented p38 and JNK phosphorylation. Pretreatment with 2 specific inhibitors of p38 and JNK, SB203580 and SP600125, respectively, resulted in a decrease in S. aureus‑induced proinflammatory gene expression levels compared with those observed in the SFN‑pretreated macrophages. Furthermore, THP‑1‑derived macrophages pretreated with SB203580 or SP600125 prior to bacterial infection exhibited a significant inhibition in intracellular S. aureus survival. In conclusion, we hypothesize that concomitant targeting of the p38/JNK‑inflammatory response and the S. aureus‑induced apoptosis with SFN may be a promising therapeutic approach in S. aureus infection.

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