Diabetic wound healing presents a unique and complex challenge due to the impaired cellular and molecular functions associated with diabetes. Chronic wounds in diabetic patients are characterized by prolonged inflammation, reduced angiogenesis, and impaired collagen deposition, which significantly hinder the healing process. This comprehensive review focuses on the innovative applications of designer cytokines in precision therapy for diabetic wound healing, emphasizing the remarkable advancements made in overcoming the limitations of natural cytokines, such as their short half-life, potential cytotoxicity, and lack of specificity. We begin by detailing the intricate biological characteristics of diabetic wounds and the essential role that cytokines play in orchestrating the healing process. The review critically examines the constraints of natural cytokines and traces the evolution of synthetic alternatives, with a particular emphasis on peptide-based and nucleic acid-based artificial cytokines. Advanced strategies for designing these artificial cytokines are discussed, including molecular modifications, functional enhancements, and specificity improvements to better target pathological conditions in diabetic wounds. Furthermore, we explore the utilization of synthetic biology techniques to engineer effective cytokine-based therapies. The promising therapeutic potential of rationally designed cytokines is highlighted, showcasing their ability to modulate the wound microenvironment, enhance tissue regeneration, and reduce chronic inflammation. This review not only provides valuable perspectives on the future research directions but also offers insights into the potential clinical applications of these innovative therapies, aiming to significantly improve the outcomes for patients suffering from diabetic wounds.

Our immune system acts to protect us in times of stress and traumatic injury. As part of the immune response, the body produces various cytokines, which mediate or modulate immune functions. Such cytokines include tumor necrosis factor (TNF) and interleukin 6 (IL-6) and IL-17. These cytokines can also act on the nervous system to influence pain perception. TNF-α triggers an inflammatory response and two forms of programmed cell death, apoptosis and necroptosis, depending on the pathological state. For individuals with chronic conditions relating to immune deficiency, the actions of these cytokines can present as chronic pain states, significantly altering quality of life. One attractive potential solution for treating this immune linked pain is by altering signaling pathways of pain-enhancing cytokines. Infliximab and etanercept are TNF inhibitors that are currently on the market for use in the treatment of chronic pain. Secukinumab and tocilizumab serve as IL inhibitors, utilized for a similar purpose. These novel immunotherapies have shown efficacy in numerous clinical studies with acceptable side effect profiles. In this review, we summarize the pharmacological profiles of these drugs and discuss their usage in treating chronic pain.

Keratinocytes play an integral role in the human epidermis, serving as a barrier between the internal and external environment. They are immune-competent cells involved in both innate and adaptive cutaneous immune responses, crucial for maintaining skin integrity. Keratinocytes are essential for epidermal repair, facilitating proliferation and re-epithelialization following injury. They secrete pro-inflammatory markers such as cytokines and chemokines, which promote the recruitment of inflammatory cells like polymorphs and macrophages to the site of skin injury. The immune response mediated by keratinocytes involves signaling molecules like tumor necrosis factor (TNF), interleukin (IL)-1β, and IL-6. Langerhans cells respond to factors secreted by keratinocytes, migrating towards draining lymph nodes to activate T cells and initiate an adaptive immune response. Additionally, keratinocytes express Toll-like receptors (TLRs), enabling them to detect molecular patterns of pathogens. Recent studies have focused on understanding these interactions of keratinocytes to develop therapeutic strategies for managing various skin diseases. Genetic defects in keratinocytes underlie conditions like psoriasis. We also discuss the role of keratinocytes and the effect of neuro-endocrinal signaling and interventions, associated corticosteroidogenic pathways, and response to UV radiations to maintain a state of homeostasis. This article underlines and improves our understanding of the immune function of keratinocytes, which is crucial for developing more effective therapies against skin diseases.

The male reproductive immune system plays a pivotal role in safeguarding sperm from immune attacks and preventing the incursion of foreign pathogens. Nucleotide-binding and oligomerization domain-like receptors (NOD-like receptors, NLRs) family protein domain containing 3 (NLRP3) is a cytoplasmic sensor binding to the inflammasome and critically involved in inducing innate immunity in the testes. It also has a substantial impact on male reproductive immunity, which is closely associated with male infertility stemming from disorders related to the male reproductive immune system. This review introduces the distinct characteristics of the NLR family, elucidates the activation pathways and factors of NLRP3 inflammasomes, and discusses how they participate in male reproductive immune diseases such as bacterial orchitis, autoimmune orchitis, varicocele, and epididymitis. In bacterial orchitis, elevated levels of NLRP3 inflammasomes exacerbate the testicular inflammatory injury and lead to decreased testosterone, thus contributing to male infertility. In autoimmune orchitis, the NLRP3 inflammasomes inhibit testosterone synthesis by decreasing the expression of cytochrome P450, thereby impacting male reproductive function. Therefore, targeting NLRP3 could offer novel immunological strategies for the clinical treatment of male infertility.

Interleukin-6 (IL-6) plays a critical role in the pathogenesis of various chronic inflammatory diseases, tracked across numerous fields of research. Despite this, a crucial aspect often overlooked in studies is the differentiation between IL-6 classic-signaling and trans-signaling, leading to potential confounding of their findings; less than half of selected IL-6 studies included differentiation. This review delves into the distinction between IL-6 classic- and trans-signaling and their role in chronic inflammatory diseases and endometriosis. The unique pro-inflammatory nature of IL-6 trans-signaling, contrasted with the anti-inflammatory character of IL-6 classic-signaling, presents significant implications for research methodology, particularly in studies investigating anti-inflammatory interventions or interleukin inhibitors. Diagnostic failure to account for these distinct pathways may inadvertently misrepresent beneficial immune responses or the efficacy of interventions, posing significant challenges in predicting health outcomes. Interventions that do not differentiate these pathways could face reduced efficacy or safety. This review proposes adjustments to research methodologies and stresses the importance of careful interpretation of inflammatory markers in IL-6-related research. Examples of differentiation issues are discussed across the topics of endometriosis and multiple inflammatory diseases. By addressing this methodological issue, researchers could potentially improve patient outcomes, enhance the efficacy of interventions, and contribute to public health advancements.

The reproductive axis of male mammals implies a coordinated interaction of its three components: a population of gonadotropin-releasing hormone (GnRH)—producing neurons of the hypothalamus, gonadotropic cells of the adenohypophysis, and most distally located testes that produce male sex hormone (testosterone) and germ cells (spermatozoa). It is generally believed that for the accurate and constant realization of reproductive function, the testes must be isolated from the internal environment of the whole organism with the help of a hematotesticular barrier. The internal immune system of the testes is primarily represented by testicular macrophages. They are located primarily in the peritubular space and provide the physical organization of peritubular myoid cells into niche-like clusters that can form an environment conducive to the differentiation of spermatogonia A1 in sperm cells. The development of this complex system occurs in mammals over a long period and is determined by the timely synchronization of all its parts. Maternal immune activation (MIA) is associated with the powerful production of proinflammatory cytokines in the mother’s body and further in the placenta and fetal region. Many of these cytokines have a pleiotropic effect and act as morphogenetic factors. Thus, cytokines can influence the development of testes even in the prenatal period. The review is focused on the effect of MIA on testicular development during prenatal state and on the holistic nature of the development of the reproductive axis of mammals on the example of laboratory rodents. Laboratory rodents (especially mice) are often used to develop models of the development of certain human systems and are the generally accepted standard for the introduction of these models into medical practice.

The control of the immune system, neuroendocrine system, and energy metabolism is essential for the physiological process of male reproduction. The hypothalamic-pituitary-testicular (HPT) axis regulates the generation of gonadal steroid hormones in the testes, which in turn controls spermatogenesis. For the growth and maturation of germ cells, the immune cells and cytokines in the testes offer a safe microenvironment. The cellular reactions and metabolic activities in the testes produce energy and biosynthetic precursors that control the growth of germ cells, as well as testicular immunology and inflammation. Both inflammatory and anti-inflammatory responses depend on immune cell metabolism, which is thought to influence testicular spermatogenesis. The significance of immunometabolism in male reproduction will be underlined in this review.