Differences in the prevalence of chronic pain in women vs. men are well known, and decades of laboratory experimentation have demonstrated that women are more sensitive to pain than are men. Attention has thus shifted to investigating mechanisms underlying such differences. Recent evidence suggests that neuroimmune modulation of pain may represent an important cause of sex differences. The current Review examines the evidence for gonadal hormone modulation of the immune system, immune system modulation of pain, and interactions that might help to explain sex differences in pain. V C 2016 Wiley Periodicals, Inc.
Successful colonization by a cancer cell of a distant metastatic site requires immune escape in the new microenvironment. TNF signaling has been implicated broadly in the suppression of immune surveillance that prevents colonization at the metastatic site and therefore must be blocked. In this study, we explored how TNF signaling influences the efficiency of liver metastasis by colon and lung carcinoma in mice that are genetically deficient for the TNF receptor TNFR2. We found a marked reduction in liver metastases that correlated with a greatly reduced accumulation at metastatic sites of CD11b
Anthrax lethal toxin (LeTx) is a virulence factor secreted byBacillus anthracis and has direct cytotoxic effects on most cells once released into the cytoplasm. The cytoplasmic delivery of the proteolytically active component of LeTx, lethal factor (LF), is carried out by the transporter component, protective antigen, which interacts with either of two known surface receptors known as anthrax toxin receptor (ANTXR) 1 and 2. We found that the cytoplasmic delivery of LF by ANTXR2 was mediated by cathepsin B (CTSB) and required lysosomal fusion with LeTxcontaining endosomes. Also, binding of protective antigen to ANXTR1 or -2 triggered autophagy, which facilitated the cytoplasmic delivery of ANTXR2-associated LF. We found that whereas cells treated with the membrane-permeable CTSB inhibitor CA074-Me-or CTSB-deficient cells had no defect in fusion of LC3-containing autophagic vacuoles with lysosomes, autophagic flux was significantly delayed. These results suggested that the ANTXR2-mediated cytoplasmic delivery of LF was enhanced by CTSB-dependent autophagic flux. Anthrax lethal toxin (LeTx)2 and edema toxin are two key virulence factors secreted by Bacillus anthracis, the causative agent of anthrax (1, 2). LeTx and edema toxin are composed of lethal factor (LF) or edema factor (EF), respectively, and protective antigen (PA), which functions as a cytoplasmic transporter of LF or EF. These toxins are main contributors to the clinical manifestations of anthrax and are cytotoxic to host cells once delivered into the cytoplasm. EF is an adenylate cyclase that raises cAMP levels in cells (3). LF is a metalloproteinase that targets the N-terminal end of the mitogen-activated protein kinase kinase 1-7 (MEK1-7) (except MEK5) (4 -6) and in certain mouse cells induces pyronecrosis by activating NACHTleucine-rich repeat and pyrin domain-containing protein 1b (NALP1b) (7).Incorporation of LF or EF into the cytoplasm is initiated by the binding of PA to the host cell surface through interacting with either of two known receptors: anthrax receptor 1 (ANTXR1, also known as the tumor endothelial marker 8) (8) and ANTXR2 (also known as the capillary morphogenesis gene-2) (9). Both ANTXR1 and -2 are widely distributed in human tissues and share molecular and biochemical similarities in their extracellular PA interacting domains known as von Willebrand factor A or integrin-like inserted (I) domain (10), post-translational modifications such as palmitoylation and ubiquitination of cytoplasmic domains (11), and associations with the co-receptor lipoprotein receptor-related 6 molecule (12, 13). ANTXR1 and -2 are also distinct in that ANTXR1 is highly expressed in tumor endothelial and cancer cells, and ANTXR2 has a higher binding affinity to PA and requires a lower pH to form a transmembrane pore than ANTXR1 (10,14).After binding PA to either ANTXR, a furin-like surface protease then cleaves PA at the N-terminal end to release a 20-kDa soluble fragment, yielding membrane-associated 63-kDa PA (PA 63 ) that forms a ring-shape heptameric ...
It has been reported consistently that many female chronic pain sufferers have an attenuation of symptoms during pregnancy. Rats display increased pain tolerance during pregnancy due to an increase in opioid receptors in the spinal cord. Past studies did not consider the role of non-neuronal cells, which are now known to play an important role in chronic pain processing. Using an inflammatory (complete Freund's adjuvant) or neuropathic (spared nerve injury) model of persistent pain, we observed that young adult female mice in early pregnancy switch from a microglia-independent to a microglia-dependent pain hypersensitivity mechanism. During late pregnancy, female mice show no evidence of chronic pain whatsoever. This pregnancy-related analgesia is reversible by intrathecal administration of naloxone, suggesting an opioid-mediated mechanism; pharmacological and genetic data suggest the importance of δ-opioid receptors. We also observe that T-cell-deficient ( and -null mutant) pregnant mice do not exhibit pregnancy analgesia, which can be rescued with the adoptive transfer of CD4 or CD8 T cells from late-pregnant wild-type mice. These results suggest that T cells are a mediator of the opioid analgesia exhibited during pregnancy. Chronic pain symptoms often subside during pregnancy. This pregnancy-related analgesia has been demonstrated for acute pain in rats. Here, we show that pregnancy analgesia can produce a complete cessation of chronic pain behaviors in mice. We show that the phenomenon is dependent on pregnancy hormones (estrogen and progesterone), δ-opioid receptors, and T cells of the adaptive immune system. These findings add to the recent but growing evidence of sex-specific T-cell involvement in chronic pain processing.
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