SOCS-JAK-STAT inhibitors and SOCS mimetics as treatment options for autoimmune uveitis, psoriasis, lupus, and autoimmune encephalitis

Abstract

Autoimmune diseases arise from atypical immune responses that attack self-tissue epitopes, and their development is intricately connected to the disruption of the JAK-STAT signaling pathway, where SOCS proteins play crucial roles. Conditions such as autoimmune uveitis, psoriasis, lupus, and autoimmune encephalitis exhibit immune system dysfunctions associated with JAK-STAT signaling dysregulation. Emerging therapeutic strategies utilize JAK-STAT inhibitors and SOCS mimetics to modulate immune responses and alleviate autoimmune manifestations. Although more research and clinical studies are required to assess their effectiveness, safety profiles, and potential for personalized therapeutic approaches in autoimmune conditions, JAK-STAT inhibitors and SOCS mimetics show promise as potential treatment options. This review explores the action, effectiveness, safety profiles, and future prospects of JAK inhibitors and SOCS mimetics as therapeutic agents for psoriasis, autoimmune uveitis, systemic lupus erythematosus, and autoimmune encephalitis. The findings underscore the importance of investigating these targeted therapies to advance treatment options for individuals suffering from autoimmune diseases.

Keywords: JAK-STAT; SOCS (suppressor of cytokine signaling); autoimmune encephalitis (AE); autoimmunity; inflammation; lupus; psoriasis; uveitis.

Figure 1

JAK-STAT Signaling Cascade: Key Players in Cellular Regulation and Immune Responses. Extracellular molecules, such as cytokines or growth factors, bind to cell surface receptors, activating Janus Kinases (JAKs). Activated JAKs phosphorylate Signal Transducers and Activators of Transcription (STATs) at specific tyrosine residues, forming homo- or heterodimers in the cytoplasm. STAT dimers then translocate to the cell nucleus and act as transcription factors, regulating gene expression. JAK inhibitors target JAKs. STAT inhibitors target STATs and prevent dimerization and its translocation to nucleus.

Figure 2

The specificity and redundancy of the JAK-STAT pathway. Different JAK family members are linked to specific cytokine receptors, and they trigger distinct STAT proteins within the pathway. This selective activation allows for fine-tuning of cellular responses to different stimuli. However, the JAK-STAT pathway also demonstrates redundancy, especially in certain cellular contexts. This redundancy ensures that essential functions are maintained even if one JAK-STAT axis is compromised or inhibited. For instance, various cytokines can activate both JAK1 and JAK2, leading to phosphorylation of STAT1 and STAT3, respectively. This redundancy allows cells to respond to multiple cytokines and ensures a robust and adaptable immune response.

Figure 3

The diagram depicts CIS/SOCS family proteins featuring conserved SOCS box in all of them. Notably, SOCS1 and SOCS3 exhibit unique kinase inhibitory region (KIR) which acts as a pseudo substrate.

Figure 4

Diagram illustrating the role of SOCS (Suppressor of Cytokine Signaling) in cytokine signaling. SOCS molecules act as crucial regulators, inhibiting excessive cytokine responses to maintain balanced immune function.

Figure 5

Schematic outline representing the genetic region on chromosome 16p13, encompassing CIITA-DEXI-CLEC16A-SOCS1. The genomic coordinates are sourced from Genome Reference Consortium Human Build 38.

Figure 6

JAK inhibitors and mimetics show promise in treating autoimmune disorders like uveitis, psoriasis, SLE, and AE. SOCS1-KIR peptide mimics SOCS1 to inhibit pro-inflammatory cytokines, reducing uveitis. In psoriasis, characterized by the infiltration of immune cells and excessive keratinocyte proliferation, the action of SOCS1 and the PS-5 peptide involves the inhibition of pro-inflammatory molecules through the targeting of JAK2. In SLE, SOCS1-KIR treatment alters lymphocyte phenotype, potentially mitigating SLE pathology. SOCS1 mimetic has not been tested for AE.

Figure 7

Roadmap detailing the discovery and approval of Janus kinase inhibitors, highlighting the key milestones and stages in the process.