Type I and type III interferons (IFNs) share several properties in common, including the induction of signaling pathways, the activation of gene transcripts, and immune responses, against viral infection. Recent advances in the understanding of the molecular basis of innate and adaptive immunity have led to the re-examination of the role of these IFNs in autoimmune diseases. To date, a variety of IFN-regulated genes, termed IFN signature genes, have been identified. The expressions of these genes significantly increase in systemic lupus erythematosus (SLE), highlighting the role of type I and type III IFNs in the pathogenesis of SLE. In this review, we first discussed the signaling pathways and the immunoregulatory roles of type I and type III IFNs. Next, we discussed the roles of these IFNs in the pathogenesis of autoimmune diseases, including SLE. In SLE, IFN-stimulated genes induced by IFN signaling contribute to a positive feedback loop of autoimmunity, resulting in perpetual autoimmune inflammation. Based on this, we discussed the use of several specific IFN blocking strategies using anti-IFN-α antibodies, anti-IFN-α receptor antibodies, and IFN-α-kinoid or downstream small molecules, which intervene in Janus kinase (JAK)-signal transducer and activator of transcription (STAT) pathways, in clinical trials for SLE patients. Hopefully, the development of novel regimens targeting IFN signaling pathways will shed light on promising future therapeutic applications for SLE patients.

Innate immune cells monitor invading pathogens and pose the first-line inflammatory response to coordinate with adaptive immunity for infection removal. Innate immunity also plays pivotal roles in injury-induced tissue remodeling and the maintenance of tissue homeostasis in physiological and pathological conditions. Lipid metabolites are emerging as the key players in the regulation of innate immune responses, and recent work has highlighted the importance of the lipid metabolite palmitate as an essential component in this regulation. Palmitate modulates innate immunity not only by regulating the activation of pattern recognition receptors in local innate immune cells, but also via coordinating immunological activity in inflammatory tissues. Moreover, protein palmitoylation controls various cellular physiological processes. Herein, we review the updated evidence that palmitate catabolism contributes to innate immune cell-mediated inflammatory processes that result in immunometabolic disorders.

Systemic lupus erythematosus (SLE) is a complex, heterogeneous, systemic autoimmune disease involving a wide array of aberrant innate and adaptive immune responses. The immune microenvironment of SLE promotes the metabolic reprogramming of immune cells, leading to immune dyshomeostasis and triggering autoimmune inflammation. Different immune subsets switch from a resting state to a highly metabolic active state by alternating the redox-sensitive signaling pathway and the involved metabolic intermediates to amplify the inflammatory response, which is critical in SLE pathogenesis. In this review, we discuss abnormal metabolic changes in glucose metabolism, tricarboxylic acid cycle, and lipid and amino acid metabolism as well as mitochondrial dysfunction in immune cells in SLE. We also review studies focused on the potential targets for key molecules of metabolic pathways in SLE, such as hypoxia-inducible factor-1α, mammalian target of rapamycin, and AMP-activated protein kinase. We highlight the therapeutic rationale for targeting these pathways in treating SLE and summarize their recent clinical applications in SLE.

Atopic dermatitis (AD) is a chronic inflammatory skin disorder marked by intricate interplay among skin barrier dysfunction, immune dysregulation, and microbial dysbiosis. While therapeutic advancements targeting T helper 2 (Th2) cytokines, such as interleukin (IL)-4 and IL-13, and the Janus kinase/signal transducer and activator of transcription (JAK/STAT) pathway have yielded promising outcomes, a significant proportion of patients still experience inadequate relief, particularly from persistent pruritus. Achieving minimal disease activity remains an unmet clinical priority and a cornerstone of effective AD management. This review provides an in-depth analysis of current therapeutic approaches and integrates findings from recent biologic studies, with a particular focus on innovative strategies under active investigation. These approaches include targeting components of the innate immune system, such as thymic stromal lymphopoietin (TSLP) and IL-1 family cytokines; the adaptive immune system, including OX40-OX40L interactions and Th17- and Th22-related cytokines; and mechanisms associated with pruritus, such as IL-31, histamine receptors, and neurokinin 1 receptor. Emerging insights underscore the transformative potential of personalized therapeutic regimens tailored to the distinct endotypes and severity of AD. Advances in deciphering the pathogenesis of AD are unlocking unprecedented opportunities for precision medicine, offering renewed hope for improved outcomes in this multifaceted and heterogeneous condition.

The effector function of T cells is critical for regulation of the initiation and progression of autoimmune diseases; whereas the T cell activation and homeostasis are tightly controlled by signals from T cell receptor (TCR). The early TCR signaling pathways are dependent on rapid phosphorylation and dephosphorylation of multiple signaling proteins in the TCR complex. These processes are tightly regulated by the interplay between protein kinases and phosphatases, leading to T cell activation. Genetic polymorphisms of these kinases or phosphatases have been linked to an increased susceptibility to autoimmune disorders in humans. Mice with deficiencies in these corresponding genes often exhibit T cell hyper-reactivity and autoimmune phenotypes in animal models. Tyrosine phosphatases have been demonstrated to alter T cell fate by negatively regulating early TCR signaling. Therefore, the tyrosine phosphatases that regulate TCR signaling are emerging as potential therapeutic targets to modulate T cell responses for the treatment of autoimmune diseases. In this review, we provide an overview of the current progress and perspectives of tyrosine phosphatases that regulate TCR signaling in T cell activation, and their potential as therapeutic targets for autoimmune diseases.