AUTHOR=Mayavannan Animamalar , Shantz Emily , Haidl Ian D. , Wang Jun , Marshall Jean S. 

TITLE=Mast cells selectively produce inflammatory mediators and impact the early response to Chlamydia reproductive tract infection

JOURNAL=Frontiers in Immunology

VOLUME=14

YEAR=2023

URL=https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2023.1166068

DOI=10.3389/fimmu.2023.1166068

ISSN=1664-3224

ABSTRACT=<sec><title>Introduction</title><p><italic>Chlamydia trachomatis</italic> (<italic>C. trachomatis</italic>) is a Gram-negative obligate intracellular bacterium that causes reproductive tract complications in women, including ectopic pregnancies and tubal factor infertility. We hypothesized that mast cells, which are common at mucosal barriers, may contribute to responses to <italic>Chlamydia</italic> infection and aimed to define human mast cell responses to <italic>C. trachomatis</italic>.</p></sec><sec><title>Methods</title><p>Human cord blood-derived mast cells (CBMCs) were exposed to <italic>C. trachomatis</italic> to assess bacterial uptake, mast cell degranulation, gene expression, and production of inflammatory mediators. The role of formyl peptide receptors and Toll-like receptor 2 (TLR2) were investigated using pharmacological inhibitors and soluble TLR2. Mast cell-deficient mice and littermate controls were used to examine the <italic>in vivo</italic> role of mast cells in influencing the immune response to <italic>Chlamydia</italic> infection in the female reproductive tract.</p></sec><sec><title>Results</title><p><italic>C. trachomatis</italic> bacteria were taken up by human mast cells but did not replicate efficiently inside CBMCs. <italic>C. trachomatis</italic>-activated mast cells did not degranulate but maintained viability and exhibited cellular activation with homotypic aggregation and upregulation of ICAM-1. However, they significantly enhanced the gene expression of <italic>IL1B</italic>, <italic>CCL3</italic>, <italic>NFKB1</italic>, <italic>CXCL8</italic>, and <italic>IL6</italic>. Inflammatory mediators were produced, including TNF, IL-1β, IL-1RA, IL-6, GM-CSF, IL-23, CCL3, CCL5, and CXCL8. Endocytic blockade resulted in reduced gene expression of <italic>IL6</italic>, <italic>IL1B</italic>, and <italic>CCL3</italic>, suggesting <italic>C. trachomatis</italic> induced mast cell activation in both extracellular and intracellular locations. The IL-6 response to <italic>C. trachomatis</italic> was reduced when CBMCs were treated with <italic>C. trachomatis</italic> coated with soluble TLR2. Mast cells derived from TLR2-deficient mice also demonstrated a reduced IL-6 response to <italic>C. muridarum</italic>. Five days following <italic>C. muridarum</italic> infection, mast cell-deficient mice showed attenuated CXCL2 production and significantly reduced numbers of neutrophils, eosinophils, and B cells in the reproductive tract when compared with mast cell-containing littermates.</p></sec><sec><title>Discussion</title><p>Taken together, these data demonstrate that mast cells are reactive to <italic>Chlamydia</italic> spp. through multiple mechanisms that include TLR2-dependent pathways. Mast cells also play an important role in shaping <italic>in vivo</italic> immune responses in <italic>Chlamydia</italic> reproductive tract infection through both effector cell recruitment and modification of the chemokine microenvironment.</p></sec>