磷脂酰丝氨酸

1、黄文龙2016-03-05Abstract: PS is also profoundly dysregulated in the tumor microenvironment and antagonizes the development of tumor immunity. In this review, we discuss the biology of PS with respect to its role as a global immunosuppressive signal and how PS is exploited to drive diverse pathological

2、processes such as infection and cancer. Finally, we outline the rationale that agents targeting PS could have significant value in cancer and infectious disease therapeutics.1.PS Asymmetry in Biological Membranes2.Mechanisms of PS Externalization during cell Stress and Apoptosis Although the biochem

3、ical landscape for PS externalization is still incomplete, recent progress in this area has emerged following the cloning and characterization of two novel scramblases; transmembrane protein 16F (TMEM16F) and Xkr8 (ced-8), that externalize PS by distinct regulatorymechanisms.Calcium-dependent phosph

4、olipid scrambling by TMEM16F. Nature 2010; 468: 834838.In contrast to TMEM16F, Xkr8 is not activated by Ca2+, but via a caspase 3/7-dependent pathway.3.Not all Externalized PS is Functionally Equivalent4.Immunological Consequences of PS;Homeostasis,Autoimmunity,and CancerIt has been known for almost

5、 two decades that apoptotic cells are potently immunosuppressiveThree kinds of interrelated pathways that signal;(i) find me (ii) eat meand (iii) tolerate me.PS is one of the primary apoptotic cell ligands that provides eat-me signals to phagocytes.Engulfed apoptotic cells induce the secretion of th

6、e anti-inflammatory cytokine interleukin-10 (IL-10) and TGF- and simultaneously decrease the secretion of the inflammatory cytokines TNF-,IL-1, and IL-125.Consequences of a Failure in Apoptotic Cell ClearanceIf clearance is impaired, apoptotic cells can undergo secondary necrosis and cause the relea

7、se of pro-inflammatory cytokines by phagocytesMultiple studies support a direct link between a failure of apoptotic cell clearance and the development of the chronic autoimmune disease systemic lupus erythematosus6.PS Receptors, Efferocytosis, and Surveyors of Immune Homeostasis7.Viruses,Protozoan P

8、arasites Utilize PS and Apoptotic Mimicry to Evade Host Immune Responses8.Externalized PS is Dysregulated in the Tumor MicroenvironmentThe non-immunogenic properties of apoptotic cells can be hijacked by tumor cells to escape immune detection by creation of a local immunosuppressive environment.In a

9、ddition, PS is markedly increased in tumors in response to chemo- and radiotherapy, which further enhances PS-mediated immunosuppression.9.Function of PS Receptors in Cancer MicroenvironmentThe TAM family: phosphatidylserinesensing receptor tyrosine kinases gone awry in cancer.NATURE REVIEWS | CANCER 201410.Pre-cli