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Protease Amplification of the Inflammatory Response Induced by Commensal Bacteria: Implications for Racial Disparity
Scott W Walsh1,2, William H Nugent3, S M Khorshed Alam3
1Department of Obstetrics and Gynecology, School of Medicine, Virginia Commonwealth University, P.O. Box 980034, Richmond, VA, 23298-0034, USA. Scott.Walsh@vcuhealth.org.
Abstract:
Decidual macrophages secrete proteases that activate protease-activated receptor 1 (PAR-1). We hypothesized that activation of the inflammatory response by bacteria is amplified by proteases, initiating labor. In addition, we hypothesized that commensal bacteria trigger an inflammatory response by activating NF-κB and TET methylcytosine dioxygenase 2 (TET2), a DNA de-methylase, via a protease amplified PAR-1, RhoA kinase (ROCK) pathway. To evaluate these hypotheses, we compared responses of mononuclear cells with Lactobacillus crispatus, prevalent in the vaginal microbiome of women of European ancestry, with L. iners and Fusobacterium nucleatum, which are more prevalent in vaginal samples collected from African-American women. Decidual tissue was collected at term not-in-labor (TNL), term labor (TL), spontaneous preterm labor (sPTL), and infected preterm labor (iPTL) and immunostained for PAR-1, TET2, and CD14. Mononuclear cells and THP-1 macrophage cells were treated with bacteria and elastase, a known activator of PAR-1. The inflammatory response was monitored by confocal microscopy of TET2 and the p65 subunit of NF-κB, as well as IL-8 production. Decidual staining for PAR-1, TET2, and CD14 increased TNL < TL < sPTL < iPTL. All treatments stimulated translocation of TET2 and p65 from the cytosol to the nucleus and increased IL-8, but L. iners and F. nucleatum caused more robust responses than L. crispatus. Inhibition of PAR-1 or ROCK prevented TET2 and p65 nuclear translocalization and increases in IL-8. Our findings demonstrate that proteases amplify the inflammatory response to commensal bacteria. The more robust response to bacteria prevalent in African-American women may contribute to racial disparities in preterm birth.
Insights
Proteases amplify bacterial inflammatory responses, potentially initiating labor. Specific bacteria, more common in African-American women, trigger stronger responses, possibly explaining preterm birth disparities.
Area of Science:
- Immunology
- Microbiology
- Reproductive Biology
Background:
- Decidual macrophages release proteases activating protease-activated receptor 1 (PAR-1).
- Bacterial activation of inflammatory pathways may be amplified by proteases, leading to labor initiation.
- Commensal bacteria might trigger inflammation via NF-κB and TET2 activation through a PAR-1, RhoA kinase (ROCK) pathway.
Purpose of the Study:
- To investigate if proteases amplify the inflammatory response to bacteria, initiating labor.
- To compare the inflammatory responses induced by different vaginal bacteria (Lactobacillus crispatus, L. iners, Fusobacterium nucleatum) in decidual cells.
- To explore the role of the PAR-1/ROCK pathway in mediating bacterial-induced inflammation and its potential contribution to preterm birth disparities.
Main Methods:
- Immunostaining of decidual tissue (TNL, TL, sPTL, iPTL) for PAR-1, TET2, and CD14.
- Treatment of mononuclear and THP-1 macrophage cells with bacteria (L. crispatus, L. iners, F. nucleatum) and elastase.
- Monitoring inflammatory markers (TET2/p65 nuclear translocation, IL-8 production) via confocal microscopy and ELISA.
- Inhibition studies using PAR-1 or ROCK inhibitors.
Main Results:
- Decidual staining for PAR-1, TET2, and CD14 increased progressively from TNL to iPTL.
- Bacterial treatments induced nuclear translocation of TET2 and p65 and increased IL-8 production.
- L. iners and F. nucleatum elicited more robust inflammatory responses than L. crispatus.
- PAR-1 or ROCK inhibition blocked these inflammatory responses.
Conclusions:
- Proteases significantly amplify the inflammatory response to commensal bacteria.
- The heightened response to bacteria prevalent in African-American women may contribute to racial disparities in preterm birth.
- The PAR-1/ROCK pathway is crucial in mediating protease-amplified inflammatory responses to bacteria in pregnancy.
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