The paradox of stress signaling in environmental disease

The development of modern human complex diseases is inescapably associated with environmental challenges, such as environmental pollution, climate change, overuse of natural resources, and built environment. From a broad view, modern human complex diseases, such as cardiovascular disease, metabolic disorders, neurodegenerative disease, and cancer, are environmental diseases.[1] Notably, disruption or dysregulation of immunity and/or metabolism are the major events that drive the pathogenesis of environmental complex diseases. This has been consolidated by overwhelming evidence provided by the biomedical research community over the past decades. Among the signaling pathways that drive immune response and metabolic changes, intracellular organelle stress responses, particularly stress signaling originated from the endoplasmic reticulum (ER) and mitochondria, play major roles in the development of inflammatory metabolic diseases or environmental diseases.[1,2] In the past decades, a large number of original research and review articles on this topic have been published. However, an important but perplex question remains: is ER or mitochondrial stress response protective or detrimental to the development of environmental complex diseases, such as atherosclerosis, type 2 diabetes mellitus, and nonalcoholic fatty liver disease? This question is raised because a big body of works showed that ER stress response or mitochondria-originated oxidative stress response contributes to or exacerbates cardiovascular and metabolic diseases, while many others observed that intracellular stress response is protective. Overviewing the literature, it becomes clear that cellular stress response, like a “double-edge” sword, plays both protective and harmful roles in the progression of inflammatory and metabolic diseases[1,3] [Figure 1]. As an indispensable defense response, the primary role of intracellular stress signaling or inflammatory response is protective, providing a survival mechanism to the stressed cells or complex organisms by helping them regain homeostasis and adapt to the stress conditions.[2,4,5] This is evidenced by the fact that major cell stress sensors are indispensable to cell physiology and survival. For example, the deficiency of the primary ER stress sensor inositol-requiring enzyme 1α (IRE1α) or PRKR-like endoplasmic reticulum kinase (PERK) leads to embryonic lethality.[6–8] Hepatic IRE1α-mediated stress signaling is required to prevent stress-induced fatty liver disease.[9,10] The liver-enriched cell stress senor CREBH functions as a major metabolic regulator of lipid and glucose metabolism in response to hepatic stress or energy demands.[11–14] The neuronal astrocyte-specific ER stress sensor old astrocyte specifically-induced substance (OASIS) is required to protect astrocytes from ER stress-induced cell death.[15,16] In addition, SMAD3-TGFβ inflammatory stress signaling plays a critical role in protecting blood vessel wall integrity.[17] Exposure to the environmental stressor fine particulate matter (PM2.5) counteracts overnutrition-caused fatty liver disease by stimulating hepatic inflammatory autophagic response.[18] On the other hand, cellular stress signaling or inflammatory responses, caused by prolonged stress or chronic disease conditions, are detrimental. The stress sensor-mediated signaling response dysregulates cell physiological processes or leads to cell death programs in specialized, professional cell types.[2,4,5] For example, the ER stress sensor IRE1α promotes macrophage inflammation and exacerbates disease progression in arthritis models.[19] Overload of cholesterols induced PERK-mediated unfolded protein response, leading to ER stress-associated macrophage cell death in an atherosclerotic model.[20,21]Figure 1: The paradox of stress response in environmental complex diseaseTo summarize, the functional paradox of stress signaling is reflected by the following scenarios: (1) to protect and remodel stressed cells or organisms from damages caused by stressors. This is the primary role of ER stress, oxidative stress, or inflammatory response. The protective effect of stress response takes place at the early stage of stress challenges. However, while stress responses help the cells adapt to and survive from stress conditions, they transform the cells into a new state that is vulnerable to further stress challenges. When the stress condition gets prolonged to a turning point, the stress response then turns to a killing signaling that drives cell death programs. (2) ER stress, oxidative stress, or inflammatory response can be induced by disease conditions as a downstream effect signaling. In this scenario, stress response acts as a detrimental signal to exacerbate the disease conditions. Like the paradox of Yin and Yang, the duration and timing of stressors and stress responses are critical for the beneficial versus detrimental effects of stress signaling in the development of environmental complex diseases [Figure 1]. The paradox of stress signaling and its protective versus detrimental effects represent a major consideration factor for therapeutic interventions by targeting stress signaling. Financial support and sponsorship The work in the Zhang lab is supported in part by the National Institutes of Health (NIH) grants R01 DK126908, DK090313, and DK132065. Conflicts of interest Dr. Kezhong Zhang is an Editor-in-Chief of Environmental Disease. The article was subject to the journal’s standard procedures, with peer review handled independently of this Editor and their research groups.