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Activation of the stress response in macrophages alters the M1/M2 balance by enhancing bacterial killing and IL-10 expression

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Abstract

Macrophages (Mϕs) play an important role in the inflammatory response during injury by participating in the removal of injurious stimuli, such as bacteria, and promoting tissue healing to restore homeostasis. Mϕs can acquire distinct functional phenotypes along a spectrum between two opposite stages (M1/M2) during activation. In the present study, we induced a stress response in Mϕs via heat shock (HS) and found that it incurred an increase in phagocytosis (1.6-fold, P < 0.05) and bacterial killing (2.8-fold, P < 0.01). Upon heat stress activation, Mϕs respond to group B Streptococcus (GBS) infection with lower levels of pro-inflammatory cytokines, TNF-α (2.25-fold, P < 0.01), IL-6 (7-fold, P < 0.001), and inducible nitric oxide synthase (iNOS) (2.22-fold, P < 0.05), but higher levels of the anti-inflammatory cytokine IL-10 (3.9-fold, P < 0.01). Stressed Mϕs exposed to GBS display rapid phagosome maturation, increased extracellular trap (ET) formation and elevated cathelicidin antimicrobial peptide expression (2.5-fold, P < 0.001). These findings are consistent with a heretofore uncharacterized Mϕ activation state formed in response to stress, associated with secretion of large quantities of anti-inflammatory mediators and redirection of antimicrobial mechanisms to NADPH-oxidase-independent pathways. This “friendly activation” of Mϕs is characterized by increased bactericidal activity and more rapid and controlled resolution of the inflammatory response.

Key Messages

  • Macrophages form a dual pro-bactericidal and anti-inflammatory state.

  • Stress in the setting of infection triggers friendly activation in macrophages.

  • Heat shock plus infection increases macrophage bactericidal activity.

  • Heat shock plus infection increases macrophage extracellular trap formation.

  • Heat shock plus infection increases macrophage production of cathelicidin and IL-10.

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Acknowledgments

We thank Molly Wofford for her editorial assistance. We thank Elisa McEachern and Matthew Lyes for their intellectual and experimental contributions. This work was supported through a Veterans Affairs Career Development Award (CDA)-2, BX-10-014 (PI, Laura E. Crotty Alexander), The Hartwell Foundation Biomedical Research Fellowship (Laura E. Crotty Alexander), University of California San Diego Academic Senate Grant (PI, Virginia L. Vega), and GM R01 098455 and GM R25 083275 grants (PI, Antonio De Maio).

Conflict of interest

The authors have no financial conflicts of interest.

Authors’ contribution

LECA, VLV, and JHW designed all of the experiments. LECA, VLV, WC, and JHW ran all of the experiments. LECA, VLV, JHW, VN, and ADM analyzed and interpreted all of the data and wrote the manuscript.

Author information

Authors and Affiliations

  1. Research and Development Division, SkinMedica, Inc., Carlsbad, CA, 92008, USA

    Virginia L. Vega

  2. Pulmonary and Critical Care Section, VA San Diego Healthcare System, La Jolla, CA, 92093, USA

    Laura E. Crotty Alexander & John H. Hwang

  3. Division of Pulmonary and Critical Care, School of Medicine, University of California San Diego (UCSD), La Jolla, CA, 92093, USA

    Laura E. Crotty Alexander & John H. Hwang

  4. Initiative for Maximizing Student Development, UCSD, La Jolla, CA, 92093, USA

    Wisler Charles

  5. Department of Pediatrics, School of Medicine, UCSD, La Jolla, CA, 92093, USA

    Victor Nizet

  6. Division of Pediatric Pharmacology and Drug Discovery, Skaggs School of Pharmacy, UCSD, La Jolla, CA, 92093, USA

    Victor Nizet

  7. Departments of Surgery and Neurosciences, School of Medicine, UCSD, La Jolla, CA, 92093, USA

    Antonio De Maio

  8. Center for Investigations of Health and Education Disparities, UCSD, La Jolla, CA, 92093, USA

    Antonio De Maio

  9. University of California San Diego, 9500 Gilman Drive, #0739, La Jolla, CA, 92093-0739, USA

    Antonio De Maio

Authors
  1. Virginia L. Vega
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  2. Laura E. Crotty Alexander
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  3. Wisler Charles
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  4. John H. Hwang
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  5. Victor Nizet
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  6. Antonio De Maio
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Corresponding author

Correspondence to Antonio De Maio.

Additional information

V. L. Vega and L. E. Crotty Alexander contributed equally to this work

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Vega, V.L., Crotty Alexander, L.E., Charles, W. et al. Activation of the stress response in macrophages alters the M1/M2 balance by enhancing bacterial killing and IL-10 expression. J Mol Med 92, 1305–1317 (2014). https://doi.org/10.1007/s00109-014-1201-y

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  • DOI: https://doi.org/10.1007/s00109-014-1201-y

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