JAK-STAT signaling in inflammation and stress-related diseases: implications for therapeutic interventions

Abstract

The Janus kinase-signal transducer and transcription activator pathway (JAK-STAT) serves as a cornerstone in cellular signaling, regulating physiological and pathological processes such as inflammation and stress. Dysregulation in this pathway can lead to severe immunodeficiencies and malignancies, and its role extends to neurotransduction and pro-inflammatory signaling mechanisms. Although JAK inhibitors (Jakinibs) have successfully treated immunological and inflammatory disorders, their application has generally been limited to diseases with similar pathogenic features. Despite the modest expression of JAK-STAT in the CNS, it is crucial for functions in the cortex, hippocampus, and cerebellum, making it relevant in conditions like Parkinson's disease and other neuroinflammatory disorders. Furthermore, the influence of the pathway on serotonin receptors and phospholipase C has implications for stress and mood disorders. This review expands the understanding of JAK-STAT, moving beyond traditional immunological contexts to explore its role in stress-related disorders and CNS function. Recent findings, such as the effectiveness of Jakinibs in chronic conditions such as rheumatoid arthritis, expand their therapeutic applicability. Advances in isoform-specific inhibitors, including filgotinib and upadacitinib, promise greater specificity with fewer off-target effects. Combination therapies, involving Jakinibs and monoclonal antibodies, aiming to enhance therapeutic specificity and efficacy also give great hope. Overall, this review bridges the gap between basic science and clinical application, elucidating the complex influence of the JAK-STAT pathway on human health and guiding future interventions.

Keywords: Inflammation; JAK inhibitors; JAK-STAT signaling; Neuropsychiatric disorders; Stress-related conditions; Therapeutic advancements.

Fig. 1

Cytokine signaling through the JAK-STAT pathway in physiological conditions. Note: Top: 1A—receptors IL-2 (IL-2Rαβγ); 1B—receptors γc -family cytokines; 2–gp130 subunit receptors; 3—type II cytokine receptors; 4—type I cytokine receptors. Under standard physiological conditions, the JAK-STAT pathway acts as an indispensable cellular communication mechanism. Highlighted are distinct regulatory combinations integral to its functionality, including JAK1-JAK2-JAK3/IL-2, IL-4, IL-7, IL-9, IL-15/JAK1, and JAK3. Center: Central to the depiction is the sophisticated intracellular machinery responsible for transcriptional and translational cascades, which are activated by specific cytokines. Bottom: Four cardinal roles of the JAK-STAT pathway under normal physiological conditions, undisturbed by external stressors, are elucidated: 1) Immune regulation: Modulating, differentiating, and activating immune cells. 2) Defense mechanisms: Spearheading potent antiviral and antitumor responses that determine the body's resistance to the occurrence of infectious and tumor diseases .3) Hematopoiesis: Governing the process of blood cell formation. 4) Metabolic regulation: Navigating cellular energy dynamics. In essence, this figure underscores the JAK-STAT pathway's paramount importance in cellular physiology, particularly in conditions devoid of stress

Fig. 2

JAK-STAT pathway's role in pathological conditions. The figure offers a schematic representation of the JAK-STAT pathway's role in pathological conditions, prominently depicted in the left central portion. It underscores the pathway's association with chronic stress, depression, and neurodegenerative processes. Notably, the 5-HT2A receptor is known to activate several mitogenic pathways, including JAK2-STAT3 and PKC-Ras-Raf-1-MAPK, across various cellular configurations. Concurrently, data illustrate the regulation of STAT3 expression by selective serotonin reuptake inhibitors (SSRIs), which inhibit the presynaptic serotonin reverse transporter (SERT), suggesting a regulatory feedback nexus between STAT3 and SERT expression. Generally, serotonin is posited to modulate JAK-STAT3 activation in specific cell types, culminating in downstream transcriptional ramifications contingent on serotonin and STAT3. Further, the right central segment of the figure illuminates molecular interactions between STAT3 and pivotal components of the serotonergic machinery. These insights accentuate the JAK-STAT pathway's role in the interface between serotonin receptors and psychiatric afflictions, offering valuable information about prospective therapeutic targets and the underlying mechanisms of these disorders. It is pivotal to highlight that such interactions against a backdrop of stress are accompanied by an elevated concentration of pro-inflammatory cytokines in the peripheral blood, attributed to the activation of immune cells, indicating chronic low-grade systemic inflammation. This interaction is depicted in the bottom left and right sections of the figure. A consequential impairment in the Blood–Brain Barrier (BBB) function leads to microglial activation and the subsequent release of pro-inflammatory cytokines, as presented in the left central segment. This cascade culminates in compromised neuronal functionality