Towards Age-Related Anti-Inflammatory Therapy: Klotho Suppresses Activation of ER and Golgi Stress Response in Senescent Monocytes

Abstract

Immunosenescence in monocytes has been shown to be associated with several biochemical and functional changes, including development of senescence-associated secretory phenotype (SASP), which may be inhibited by klotho protein. To date, it was believed that SASP activation is associated with accumulating DNA damage. However, some literature data suggest that endoplasmic reticulum and Golgi stress pathways may be involved in SASP development. Thus, the aim of this study was to investigate the role of klotho protein in the regulation of immunosenescence-associated Golgi apparatus and ER stress response induced by bacterial antigens in monocytes. We provide evidence that initiation of immunosenescent-like phenotype in monocytes is accompanied by activation of CREB34L and TFE3 Golgi stress response and ATF6 and IRE1 endoplasmic reticulum stress response, while klotho overexpression prevents these changes. Further, these changes are followed by upregulated secretion of proinflammatory cytokines, which final modification takes place exclusively in the Golgi apparatus. In conclusion, we provide for the first time evidence of klotho involvement in the crosstalk on the line ER-Golgi, which may, in turn, affect activation of SASP. This data may be useful for a novel potential target for therapy in age-related and chronic inflammatory conditions.

Golgi stress response: A regulatory mechanism of Golgi function

“…Moreover, in human monocytes, the TFE3 and CREB3 pathways of the mammalian Golgi stress response are activated with the initiation of immunosenescent-like phenotype, but this process can be inhibited by overexpression of the secrete form of klotho. 85 klotho is essential for various physiological processes, including glucose metabolism, cell proliferation, and apoptosis, especially for the normal functioning of the immune system. [86][87][88] This finding has important implications for identifying new molecular targets that could be useful in therapeutic intervention of age related and chronic inflammatory conditions.…”

Klotho as a biomarker of subclinical atherosclerosis in patients with moderate to severe chronic kidney disease

“…In this sense, the expression of Klotho in these cells has been related with the attenuation of lipopolysaccharide (LPS)-induced acute inflammation in macrophages and with the inactivation of NF-kB signaling and the promotion of M2 polarization in these cells, which infiltrates atheromatous plaques and develop a defensive and repair response to vascular damage 46,47 . Moreover, it has also been related with the suppression of the stress response of the Golgi apparatus and endoplasmic reticulum, the reduction of the levels of oxidant radicals and pro-inflammatory cytokines, as well as with an increase in the production of anti-inflammatory cytokines and the preservation of the immune function in senescent monocytes 48,49 . All these mechanisms play key roles in the inflammatory response exerted by PBCs in the atherosclerotic process and, therefore, make Klotho expression in these cells an interesting target in such scenario.…”

A Computational Approach for Defining a Signature of β-Cell Golgi Stress in Diabetes

“…In addition, the secretion of large amounts of proteins has been shown to impair GA glycosylation and transport (38), and GA morphologic changes have also been observed after viral infection, such as GA fragmentation and dispersal resulting from herpes virus infection (39). Much of the evidence for GA stress has been discerned from studies of neurodegenerative diseases (11,12,40), but GA stress has also been observed or implicated in skeletal muscle disorders (41), alcohol-induced liver disorders (42), and disorders affecting monocytes (13) and intestinal Brunner gland cells (43). Notably, monocytes and Brunner gland cells are secretory cell types, secreting cytokines (44) and mucins (45), respectively.…”

“…In this regard, ER stress has been well documented to play a role in the pathogenesis of both T1D and T2D (7)(8)(9)(10), and the tripartite ER stress response has been studied extensively, resulting in multiple well-validated protein and transcriptional markers of ER stress. The concept of GA stress has been proposed primarily in the context of neurologic disorders (11,12), but has also been suggested to occur in other secretory cells, such as monocytes (13) and Brunner gland cells (14). Several candidate GA stress markers were recently identified in other cell types and linked with GA morphologic changes observed by electron microscopy (15).…”