Myd88 Signaling Is Involved in the Inflammatory Response in LPS-Induced Mouse Epididymitis and Bone-Marrow-Derived Dendritic Cells.

Epididymitis is an epididymal inflammation that may lead to male infertility. Dendritic cells (DCs) and myeloid differentiation primary response gene 88 (Myd88) were associated with epididymitis in rodents. However, the functions of Myd88 on epididymal DCs remain unclear. This study investigated the role of Myd88 in DCs for epididymitis. The Myd88 signaling pathway, phenotypes of DC subsets, and cytokines were investigated in lipopolysaccharide (LPS)-induced epididymitis in mice. CRISPR-Cas9 was used to knockout Myd88 in bone-marrow-derived dendritic cells (BMDCs) and immortalized mouse epididymal (DC2) cell line. In the vivo experiments, levels of the proinflammatory cytokines IL-1α, IL-6, IL-17A, TNF-α, IL-1ß, MCP-1, and GM-CSF, mRNA for MyD88 related genes, and the percentages of monocyte-derived DCs (Mo-DCs) were significantly elevated in mice with epididymitis. In the vitro experiments, LPS significantly promoted the apoptosis of BMDCs. In addition, the concentration of inflammatory cytokines in BMDCs and DC2s were increased in the LPS group, while decreasing after the knockout of Myd88. These findings indicate that Myd88 on DCs is involved in the inflammation of epididymitis in mice, which may be a potential target for better strategies regarding the treatment of immunological male infertility.

Follicular helper T lymphocytes in the endometria of patients with reproductive failure: Association with pregnancy outcomes and inflammatory status of the endometria.

PROBLEM: The phenotypes and functions of B and CD4+ T-helper cell subsets during chronic inflammation of the endometria remain largely unexplored. This study aimed to investigate the characteristics and functions of follicular helper T (Tfh) cells to understand the pathological mechanisms of chronic endometritis (CE). METHOD OF STUDY: Eighty patients who underwent hysteroscopic and histopathological examinations for CE were divided into three groups-those with positive results for hysteroscopy and CD138 staining (DP), negative results for hysteroscopy but positive CD138 staining (SP), and negative results for hysteroscopy and CD138 staining (DN). The phenotypes of B cells and CD4+ T-cell subsets were analyzed using flow cytometry. RESULTS: CD38+ and CD138+ cells were mainly expressed in the non-leukocyte population of the endometria, and the endometrial CD19+ CD138+ B cells were fewer than the CD3+ CD138+ T cells. The percentage of Tfh cells increased with chronic inflammation in the endometria. Additionally, the elevated percentage of Tfh cells correlated with the number of miscarriages. CONCLUSIONS: CD4+ T cells, particularly Tfh cells, may be critical in chronic endometrial inflammation and affect its microenvironment, thereby regulating endometrial receptivity, compared to B cells.

Signal Transducer and Activator of Transcription 3 Hyperactivation Associates With Follicular Helper T Cell Differentiation and Disease Activity in Rheumatoid Arthritis.

Follicular helper T (Tfh) cells are the specialized CD4+ T cell subset that supports B cells to produce high-affinity antibodies and generate humoral memory. Not only is the function of Tfh cells instrumental to mount protect antibodies but also to support autoantibody production and promote systemic inflammation in autoimmune diseases. However, it remains unclear how the activation of Tfh cells is driven in autoimmune diseases. Here, we report that in patients with rheumatoid arthritis (RA), excessive generation of CXCR5+PD-1+ memory Tfh cells was observed and the frequency of memory Tfh cells correlated with disease activity score calculator for RA (DAS28). The differentiation of Tfh cells is dependent on signal transducer and activator of transcription 3 (STAT3), the key transcription factor downstream of cytokine signal pathways. A drastic increase of phosphorylated STAT3 (pSTAT3) in CD4+ T cells were detected in RA patients who also produced larger amounts of STAT3-stimulating cytokines, including IL-6, IL-21, IL-10, and leptin than those of healthy controls. Importantly, the phosphorylation status of STAT3 in CD4+ T cells positively correlated with the plasma concentration of IL-6 and the frequency of memory Tfh cells. This study reveals an IL-6-pSTAT3-Tfh immunoregulatory axis in the pathogenesis of RA and reinforces its candidature as biomarkers and targets for diagnosis and therapy.