Editorial: Modulation of Pro-Inflammatory Signaling by Interferons

René Huber^1*Korbinian Brand^1*Kyung-Hyun Park-Min^2*

• ¹Medizinische Hochschule Hannover, Hanover, Germany
• ²Hospital for Special Surgery, New York, United States

Keywords: Interferons, cytokines, mutual regulation, pro-inflammatory signaling, interferon-14 stimulated genes, inflammation, autoimmunity, interferon-associated diseases 15 16Interferons (IFNs) are crucial regulators of the immune response mediating both pro-and anti-17 inflammatory effects (1, 2). To date, the human IFN family comprises type I (IFN-I: IFN-α, -β, -ε, -κ, 18 and -ω), II (IFN-γ), and III IFNs (IFN-λ). Following binding to their receptors, they activate intracellular 19 signaling, predominantly the Jak-STAT pathway, and induce the expression of a broad range of 20 interferon-stimulated genes (3). However, due to the variety of potentially activated cascades, shared 21 target promoter elements, and the specific characteristics of interferon-responsive cells (among 22 other things), different (types of) interferons may have distinct as well as overlapping functions. While 23 their canonical function is the mediation of anti-viral activity and the defense against microbial 24 infections, IFNs further proved to be involved in anti-tumor immunity, autoimmunity, cell 25 development, tissue protection, homeostasis, and metabolism (1,4).Under both physiological and pathophysiological conditions, however, interferons do not act 27 on target cells alone, but are part of a complex cocktail of cytokines, chemokines, growth factors, and 28 other mediators, whose interaction defines the reaction of the cells to the specific stimulatory 29 situation (5). Alterations in the proper orchestration of this immunomodulatory network may result 30 in the dysregulations of the respective response, thus enabling infectious, inflammatory, or malignant 31 diseases. Li et al., for instance, examine this aspect in the field of osteoimmunology, an 32 interdisciplinary area studying the crosstalk between the immune system and the skeletal system. In 33 their review, they focus on the intricate and in part contradictory impact of IFN-γ on bone remodeling 34 during osteoporosis, a systemic disease characterized by low bone mass and an increased risk of 35 fracture (6). The authors recognize in detail the multifaceted contribution of IFN-γ to osteoblast differentiation and the limitation of osteoclast formation, but also consider its capacity to indirectly 37 increase the bone-resorbing activity of mature osteoclasts. Thus, IFN-γ exhibits both osteoprotective 38 and osteodestructive properties. In the case of osteoporosis, however, IFN-γ appears to account for 39 a net loss of bone mass, although its effects may be complex and disease stage-specific. 40The As illustrated, IFNs are of decisive importance in the development of (patho-)physiological 58 states associated with inflammation, but their impact cannot be understood without knowledge on 59 the events regulating their expression (1) or the interaction with other mediators (5). Therefore, Yu 60 and colleagues have a closer look on interferon regulatory factor (IRF)5, a transcription factor that -61 due to the functional differentiation from its relatives -contributes to the expression of both IFN-I 62 and pro-inflammatory cytokines/chemokines. The authors characterize IRF5 as a potent player in 63 antiviral immunity, but also as a driver of inflammatory and autoimmune diseases such as 64 inflammatory bowel disease, SLE, or rheumatoid arthritis. Interestingly, IRF5 appears to fan 65 inflammation-associated malignancies, while it may adopt the role of a tumor suppressor in other 66 forms of cancer, depending on the type of affected cells and tissues. Due to its involvement in these 67 and other diseases, IRF5 can be regarded as a therapeutic target, and influence on TNF expression or the symptomatic of the infection, carriers of the rs179008 major allele 78 exhibited increased IFN-α amounts, while the minor allele of rs3853839 was associated with higher 79 TLR7 levels. Thus, the rs179008 major and the rs3853839 minor allele may have protective effects by 80 supporting antiviral defense. Finally, Kaminiów and co-workers investigate the association of two 81SNPs located in introns of the IFN-γ gene, rs2430561 (T/A) and rs1861494 (A/G), with the serological 82 response in early treated syphilis patients. In both cases, homozygous carriers of the major alleles 83 showed higher IFN-γ levels in combination with serological cure. In contrast, the homozygous minor 84 genotype was associated with low IFN-γ levels and a (persisting) serofast state, an observation 85 suggesting a predisposition for the development of serofast syphilis.In summary, this article collection adds a few more mosaic tiles to a complex and still 87 expanding topic and thus complements the picture we have of IFNs, their properties, and their 88 interrelationship with other factors. The manuscripts included thus enhance our understanding of 89 the molecular mechanisms underlying the diverse effects of IFNs under multiple conditions. 90 91