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Problem: In women of reproductive age, endometriosis may contribute to dysmenorrhea, chronic pelvic pain, dyspareunia, infertility, adenomyosis, and endometrial ovarian cyst (EOC). Recent studies have shown that chronic inflammation occurs in the pelvis of endometriosis patients and that this inflammation is exacerbated by immunosuppression, leading to survival endometrial debris. However, the detailed immunological mechanisms underlying the aggravation of inflammation and immunosuppression in endometriosis patients remain unclear. Method of Study: We investigate the alarmins (high‐mobility group box‐1, IL‐33, IL‐1α, and S100B protein), proinflammatory cytokines (IL‐6 and IL‐1β), and immune cells (CD8+ T cells, CD4+ T cells, natural killer cells, natural killer T cells, dendritic cells, and macrophages) in peritoneal fluid of patients with EOC using enzyme‐linked immunosorbent assay, electrochemiluminescence, and flow cytometry. Then, we analyzed the correlation between these factors and the aggravating indicators of endometriosis, tumor size and revised American Society for Reproductive Medicine (r‐ASRM) score. Results: Unexpectedly, there was no correlation between each alarmin level and aggravating indicators. However, the expression of pattern recognition receptors, toll‐like receptor 4, and receptor of advanced glycation end‐products on macrophages was inversely correlated with aggravating indicators. Conclusions: The aggravation of endometriosis is associated with a decrease in alarmin receptors but not alarmin levels. Investigation of innate immune systems, such as alarmins and their receptors, may help elucidate new mechanisms of endometriosis. [ABSTRACT FROM AUTHOR]

Damage-associated molecular patterns (DAMPs) trigger sterile inflammation after tissue injury, but the mechanisms underlying the resolution of inflammation remain unclear. In this study, we demonstrate that common DAMPs, such as high-mobility-group box 1 (HMGB1), peroxiredoxins (PRXs), and S100A8 and S100A9, were internalized through the class A scavenger receptors MSR1 and MARCO in vitro. In ischemic murine brain, DAMP internalization was largely mediated by MSR1. An elevation of MSR1 levels in infiltrating myeloid cells observed 3 d after experimental stroke was dependent on the transcription factor Mafb. Combined deficiency for Msr1 and Marco, or for Mafb alone, in infiltrating myeloid cells caused impaired clearance of DAMPs, more severe inflammation, and exacerbated neuronal injury in a murine model of ischemic stroke. The retinoic acid receptor (RAR) agonist Am80 increased the expression of Mafb, thereby enhancing MSR1 expression. Am80 exhibited therapeutic efficacy when administered, even at 24 h after the onset of experimental stroke. Our findings uncover cellular mechanisms contributing to DAMP clearance in resolution of the sterile inflammation triggered by tissue injury., Author(s): Takashi Shichita (corresponding author) [1, 2, 3, 4, 5]; Minako Ito [1, 2]; Rimpei Morita [1, 2]; Kyoko Komai [1, 2]; Yoshiko Noguchi [1, 2]; Hiroaki Ooboshi [6]; Ryusuke [...]

Although Kampo—a traditional Japanese herbal medicine—contributes in the control of tumor growth in vivo in experimental animals, most of the antitumor effects are prophylactic and not therapeutic. In this study, we determined whether oral administration of an herbal mixture containing Ganoderma lucidum (WTMCGEP; Wisteria floribunda, Trapae fructus, Myristica fragrans, Coicis semen, Ganoderma lucidum, Elfvingia applanata, and Punica granatum), anecdotally used in Japan for the palliative care of patients with cancer, exhibits a therapeutic effect on tumor growth in vivo in a hypodermic murine CT26 colorectal tumor model. An in vitro tumor assay revealed that WTMCGEP extract has some direct influence over suppression of tumor growth. In wild-type BALB/c mice, WTMCGEP did not show any antitumor effect in vivo. However, in BALB-CD1d−/− mice with partly mitigated immunosuppression by reason of them being devoid of both antitumoral type I and immunosuppressive type II natural killer T (NKT) cells, WTMCGEP therapeutically suppressed tumor growth. CD8+ T cell depletion significantly accelerated tumor growth in WTMCGEP mice; therefore, its antitumor activity was primarily in a CD8+ T cell-dependent manner. Regarding immunosuppressive cells in tumor-bearing CD1d−/− mice, WTMCGEP did not influence the abundance of tumor-infiltrating CD4+ and Forkhead box protein 3+ regulatory T cells. However, it reduced both intratumoral and splenic Ly6G+ Ly6Clo polymorphonuclear myeloid-derived suppressor cells, which were most likely involved in tumor growth inhibition related to higher frequency of intratumoral CD107a+ CD8+ T cells in these mice. Overall, these data illustrate that the deficiency of NKT cells urges WTMCGEP to exert a therapeutic antitumor effect mainly through CD8+ T cells. Our efforts are the first to scientifically demonstrate the WTMCGEP's contribution to tumor immunity. [ABSTRACT FROM AUTHOR]

Post-ischemic inflammation is an essential step in the progression of brain ischemia-reperfusion injury. However, the mechanism that activates infiltrating macrophages in the ischemic brain remains to be clarified. Here we demonstrate that peroxiredoxin (Prx) family proteins released extracellularly from necrotic brain cells induce expression of inflammatory cytokines including interleukin-23 in macrophages through activation of Toll-like receptor 2 (TLR2) and TLR4, thereby promoting neural cell death, even though intracellular Prxs have been shown to be neuroprotective. The extracellular release of Prxs in the ischemic core occurred 12 h after stroke onset, and neutralization of extracellular Prxs with antibodies suppressed inflammatory cytokine expression and infarct volume growth. In contrast, high mobility group box 1 (HMGB1), a well-known damage-associated molecular pattern molecule, was released before Prx and had a limited role in post-ischemic macrophage activation. We thus propose that extracellular Prxs are previously unknown danger signals in the ischemic brain and that its blocking agents are potent neuroprotective tools., Stroke is one of the major causes of death and disability worldwide. The only globally approved treatment for ischemic stroke is tissue plasminogen activator, a time-dependent therapy that must be [...]