Impacts of Endoplasmic Reticulum Stress on Calreticulin Secretion and Innate Immunity.

ER Stress;Cell-surface Calreticulin;Phagocytosis;Inflammation;Microbiology and Immunology;Science;Immunology

Peters, Larry RobertSwanson, Joel A. ;

University of Michigan

关键词: ER Stress;    Cell-surface Calreticulin;    Phagocytosis;    Inflammation;    Microbiology and Immunology;    Science;    Immunology;   

Others  :  https://deepblue.lib.umich.edu/bitstream/handle/2027.42/89695/larryrob_1.pdf?sequence=1&isAllowed=y

瑞士|英语

来源: The Illinois Digital Environment for Access to Learning and Scholarship

【 摘 要 】

The innate immune system must differentiate homeostatic cell stress and death from that associated with danger and infection. Failure to do so can lead to inflammatory disorders and autoimmunity on one hand, or cancer and infection on the other. Various endogenous host factors are proposed to tolerize or activate the immune system in response to cell stress/death. Antigen presenting cells (APCs), in particular dendritic cells (DC), are critical in the induction and direction of the immune response, including responses to cell stress/death. Many endogenous molecules influence APC activation in a paracrine manner following exposure to stressed/dying cells. Conversely, stress within an APC can modulate how it directs an immune response. This thesis focuses on (1) characterizing a novel pathway of increased cell-surface expression of calreticulin that occurs concomitantly with secretion of several other endogenous proteins previously defined as immunomodulatory; (2) using this pathway to examine the abilities of ER chaperones to influence innate immune responses in the context of ER stress, with a specific focus on calreticulin; (3) measuring the ability of cell-surface calreticulin to promote phagocytic uptake of ER stressed cells by DC; (4) comparing cytokine production by DCs experiencing two different forms of ER stress.Much recent attention has been focused on the ability of cell-surface calreticulin to induce anti-tumor immune responses to dying tumor cells. We characterize a novel stimulus, thapsigargin, and the related pathway for the induction of high levels of cell-surface calreticulin. Thapsigargin depletes ER calcium, inducing ER stress and a general handicap in ER retention mechanisms. Thapsigargin-treated cells secrete several ER chaperones previously characterized as immunomodulatory. We show that extracellular calreticulin does not modulate the ability of DCs to secrete inflammatory cytokines under sterile conditions or in the presence of an innate immune stimulus such as LPS. On the other hand, DC phagocytosed ER-stressed target cells significantly more than untreated control targets. Furthermore, the presence of cell-surface calreticulin on target cells correlated with their enhanced phagocytic uptake. Together these findings demonstrate that calcium depletion in the ER interferes with retention mechanisms of ER-resident proteins and impacts phagocytic uptake of cells in a calreticulin-dependent manner.