The cellular stress response may be induced by a wide-variety of different stimuli, many of which are often secondary to infectious or neoplastic processes. Given the frequently ominous origins of phenomena like DNA damage, metabolic perturbation, anomalous cell cycle regulation, inappropriate translation, and aberrant protein folding, it is intuitive that characteristic events like these should also trigger a heightened state of immune surveillance. Such early warning signals serve to alert both innate and adaptive immunity of potential threats before direct detection by immunocytes via Pattern Recognition Receptor (PRR) signaling or, in the case of adaptive immunity, by T cell receptor (TCR) interaction with high affinity peptide epitopes presented by MHC. In this issue, a variety of different authors offer insight into the mechanisms by which stressed cells interface with the immune system, thereby giving advanced warning of potential hazards prior to detection of classical danger.
In a recent issue of the International Reviews of Immunology, Rausch and Sertil (Citation1) discussed the endoplasmic reticulum (ER) stress response and the role it plays in the regulation of tumor immunity. The ER is the primary organelle governing the biosynthesis and proper folding of a broad array of cellular proteins. When proper protein folding is disrupted as often occurs in the hypoxic and/or glucose-starved conditions that accompany oncogenesis, the ER stress response is activated and subsequently serves as both ying and yang in control of downstream antitumor responses.
In the current issue of the journal, we continue to feature the interface between cellular stress and immunity. Liang et al focus on the enigmatic multi-aminoacyl tRNA synthetase (mARS) complex and its equally enigmatic structural protein mARS complex interacting multifunctional protein 1 (AIMp1). Though composed of aminoacyl-tRNA synthetases, the mARS complex appears to have little to do with the direct translation of mRNA into polypeptides. Rather, the mARS appears to permit detection of cell stress related to transformation, a process that can be neoplastic or infectious in origin. Detection of such stress leads to release of the mARS structural component AIMp1, a pleiotropic signaling molecule with cytokine and chemokine-like properties that subsequently engages the immune system through a variety of different mechanisms.
Bhattacharya and Eissa describe the importance of autophagy, the critical cellular housekeeping process that recycles damaged and aging organelles. Given its central role in cellular homeostasis, autophagy can act as an integrative, global mechanism of stress detection and plays a critical role in the regulation of immune function in response to the stress associated with infection, inflammation, and autoimmunity.
The authors touch upon important yet underappreciated topics in immunology, and the work presented herein provides a critical window into the extensive crosstalk that exists between the innate and adaptive immune systems and homeostasis at the cellular level.
In this issue, we are also hosting several reviews on other topics. Sido et al discuss the role of endocannabinoid activation of peripheral CB1 receptors in the regulation of autoimmune disease. Several cannabinoid receptors are expressed on immune cells: CB1, CB2, TRPV-1, and GPR55. To date, the expression profile of CB2 receptors and their role in autoimmunity are well characterized. In addition, the impact of the endogenous cannabinoids (AEA, 2-AG, PEA, and virodamine) on immune cells, and their role in the prevention and treatment of inflammatory and autoimmune diseases are an intense area of investigation. In contrast to CB2 receptors, the importance of CB1 receptors in immunological disorders has often been overlooked especially because they are not highly expressed on naive immune cells. This review by Nagarkatti et al also discusses the effect of endocannabinoids on CB1 receptors in T cell driven autoimmune diseases.
Ge et al discuss the roles of lysosomes in inflammation and autoimmune diseases. Lysosomes perform a wide range of functions, from housekeeping to interfacing with the immune system. This review describes lysosomal regulation of the inflammatory glucocorticoid signaling pathways, and summarizes the roles of lysosomes in negatively or positively modulating the production of inflammatory cytokines. Ge et al also review the characteristic changes in lysosomal hydrolases and membrane proteins in common autoimmune diseases.
Last but not least, Panneerselvam and Ding discuss the role of the “Sterile alpha and armadillo motif-containing protein” (SARM) in antiviral immune defense and cellular apoptosis. SARM is a recently identified Toll-interleukin receptor (TIR) domain-containing cytosolic protein. Classified as a member of the Toll-like receptor (TLR) adaptor family, SARM has a pleiotropic and complex effect on TLR-signaling. Recent studies have highlighted the significant functional role of SARM in mediating apoptosis and antiviral innate immune response. In this review, the authors provide an update on the known role of SARM in context of TLR signaling, and define questions that remain to be addressed.
Declaration of Interest
The author reports no conflict of interest.The author alone is responsible for the content and writing of the article.