Architecture of antimicrobial skin defense Publication date: Available online 15 August 2019 Source: Cytokine & Growth Factor Reviews Author(s): Kamila Kwiecien, Aneta Zegar, James Jung, Piotr Brzoza, Mateusz Kwitniewski, Urszula Godlewska, Beata Grygier, Patrycja Kwiecinska, Agnieszka Morytko, Joanna Cichy Abstract The skin is the largest and the most exposed organ in the body and its defense is regulated at several anatomical levels. Here, we explore how skin layers, including the epidermis, dermis, adipose tissue, and skin appendages, as well as cutaneous microbiota, contribute to the function of skin antimicrobial defense. We highlight recent studies that reveal the differential and complementary responses of skin layers to bacterial, viral, and fungal infection. In particular, we focus on key soluble mediators in the layered skin defense, such as antimicrobial peptides, as well as on lipid antimicrobials, cytokines, chemokines, and barrier-maintaining molecules. We include our own analyses of publicly available transcriptomic datasets of human skin to map the involvement of antimicrobial peptides in skin protection under both steady state and infectious conditions. Furthermore, we explore the versatility of the mechanisms underlying skin defense by highlighting the role of the immune and nervous systems in their interaction with cutaneous microbes, and by illustrating the multifunctionality of selected antimicrobial peptides in skin protection. Graphical abstract

Regulatory interplay between deubiquitinating enzymes and cytokines Publication date: August 2019 Source: Cytokine & Growth Factor Reviews, Volume 48 Author(s): Bean Woo, Kwang-Hyun Baek Abstract Deubiquitinating enzymes (DUBs) are cysteine protease proteins that reverse the ubiquitination by removing ubiquitins from the target protein. With over 100 DUBs identified and categorized into at least 7 families, many DUBs interact with one or more cytokines, influencing cellular processes, such as antiviral responses, inflammatory responses, apoptosis, etc. While some DUBs influence cytokine pathway or production, some DUBs are cytokine-inducible. In this article, we summarize a list of DUBs, their interaction with cytokines, target proteins and mechanisms of action. Graphical abstract

CD14: Biology and role in the pathogenesis of disease Publication date: August 2019 Source: Cytokine & Growth Factor Reviews, Volume 48 Author(s): Zhenghao Wu, Zhenxiong Zhang, Zehua Lei, Ping Lei Abstract Human monocyte differentiation antigen CD14 is a pattern recognition receptor (PRR) that enhances innate immune responses. CD14 was first identified as a marker of monocytes to signal intracellular responses upon bacterial encounters. Given the absence of an intracellular tail, CD14 was doubted to have the signaling capacities. Later CD14 was confirmed as the TLR co-receptor for the detection of pathogen-associated molecular patterns. However, CD14 has been revealed as a multi-talented receptor. In last decade, CD14 was identified to activate NFAT to regulate the life cycle of myeloid cells in a TLR4-independent manner and to transport inflammatory lipids to induce phagocyte hyperactivation. And its influences on multiple related diseases have been further considered. In this review, we summarize advancements in the basic biology of the CD14 including its structure, binding ligands, signaling pathways, and its roles in the pathogenesis of inflammation, atherosclerosis, tumor and metabolic diseases. We also discuss the therapeutic potential of targeting the CD14 in related diseases. Graphical abstract

The dynamic interactions between the stroma, pancreatic stellate cells and pancreatic tumor development: Novel therapeutic targets Publication date: August 2019 Source: Cytokine & Growth Factor Reviews, Volume 48 Author(s): Batoul Farran, Ganji Purnachandra Nagaraju Abstract The stroma is a main driver of metastasis and aggressiveness in pancreatic cancer (PC), one of the deadliest malignancies worldwide. Pancreatic stellate cells (PSCs) form approximately 50% of the pancreatic tumor stroma, causing desmoplasia, extracellular matrix (ECM) deposition, epithelial-to-mesenchymal transition (EMT) and metastatic spread. Furthermore, activated PSCs can remodel the pancreatic tumor microenvironment (TME) via dynamic and complex interactions and feedback loops with PC cells, thus facilitating tumor growth through various signalling and immune pathways. Hence, increased understanding of these cellular cross-talks and how they shape the TME in PC might guide the development of novel treatment approaches against this stubborn and deadly malignancy that has so far resisted therapeutic advances. In this review, we will explore the role of the stroma and PSCs in PC development, invasion and metastasis, examine their interaction with PC cells and discuss potential treatment approaches aimed at targeting PSCs in order to reprogram the pancreatic tumor environment. Graphical abstract

Potential role of melatonin in autoimmune diseases Publication date: August 2019 Source: Cytokine & Growth Factor Reviews, Volume 48 Author(s): Chan-Na Zhao, Peng Wang, Yan-Mei Mao, Yi-Lin Dan, Qian Wu, Xiao-Mei Li, De-Guang Wang, Callan Davis, Wenbiao Hu, Hai-Feng Pan Abstract Autoimmune diseases are a broad spectrum of disorders involved in the imbalance of T-cell subsets, in which interplay or interaction of Th1, Th17 and Tregs are most important, resulting in prolonged inflammation and subsequent tissue damage. Pathogenic Th1 and Th17 cells can secrete signature proinflammatory cytokines, including interferon (IFN)-γ and IL-17, however Tregs can suppress effector cells and dampen a wide spectrum of immune responses. Melatonin (MLT) can regulate the humoral and cellular immune responses, as well as cell proliferation and immune mediators. Treatment with MLT directly interferes with T cell differentiation, controls the balance between pathogenic and regulatory T cells and regulates inflammatory cytokine release. MLT can promote the differentiation of type 1 regulatory T cells via extracellular signal regulated kinase 1/2 (Erk1/2) and retinoic acid-related orphan receptor-α (ROR-α) and suppress the differentiation of Th17 cells via the inhibition of ROR-γt and ROR-α expression through NFIL3. Moreover, MLT inhibits NF-κB signaling pathway to reduce TNF-α and IL-1β expression, promotes Nrf2 gene and protein expression to reduce oxidative and inflammatory states and regulates Bax and Bcl-2 to reduce apoptosis; all of which alleviate the development of autoimmune diseases. Thus, MLT can serve as a potential new therapeutic target, creating opportunities for the treatment of autoimmune diseases. This review aims to highlight recent advances in the role of MLT in several autoimmune diseases with particular focus given to novel signaling pathways involved in Th17 and Tregs as well as cell proliferation and apoptosis. Graphical abstract

Editorial Board Publication date: August 2019 Source: Cytokine & Growth Factor Reviews, Volume 48 Author(s):

The potential of adipokines as biomarkers and therapeutic agents for vascular complications in type 2 diabetes mellitus Publication date: August 2019 Source: Cytokine & Growth Factor Reviews, Volume 48 Author(s): Wei Liang, Dong dong Ye Abstract Over the past decades, there has been a major increase in type 2 diabetes (T2D) prevalence in most regions of the world. Diabetic patients are more prone to cardiovascular complications. Accumulating evidence suggests that adipose tissue is not simply an energy storage tissue but it also functions as a secretory tissue producing a variety of bioactive substances, also referred to as adipokines. The balance between pro-inflammatory adipokines and protective adipokines is disturbed in type 2 diabetes, this can be regarded as adipose tissue dysfunction which partly promote the pathogenesis of diabetes complications. In this review, we not only discuss the favorable adipokines like adiponectin, omentin, C1q tumor necrosis factor-related proteins, but also unfavorable ones like resisitin and visfatin, in the aim of finding potential biomarkers recommended for the clinical use in the diagnosis, prognosis and follow up of patients with T2D at high risk of developing cardiovascular diseases as well as leading to new therapeutic approaches. Graphical abstract

Dual faced HMGB1 plays multiple roles in cardiomyocyte senescence and cardiac inflammatory injury Publication date: June 2019 Source: Cytokine & Growth Factor Reviews, Volume 47 Author(s): Hongxiang Lu, Zhenzhen Zhang, Prince Amoah Barnie, Zhaoliang Su Abstract High mobility group box 1 (HMGB1) is constitutively expressed by many cells. In cells, HMGB1 is a transcription factor or transcription enhancer that is involved in nucleosome sliding, DNA repair, V(D)J recombination, telomere homeostasis, autophagy and viral sensing. HMGB1 can also be secreted or released by stressed cells and serves as an alarmin, cytokine or growth factor to activate the immune response. This protein facilitates CD4+ T cell differentiation and tissue repair through binding with its receptors, including toll-like receptors (TLRs) and the receptor for advanced glycation end-products (RAGE). Recent works have established that HMGB1 plays many vital functions in cardiac inflammatory injury, cardiac regeneration and remodelling. The present review addresses the novel role of HMGB1 in secretion and cardiomyocyte senescence and in the dual faced roles of HMGB1 in cardiac inflammatory injury, inflammatory resolution and cardiac regeneration and remodelling following cardiac injury. Graphical abstract

Role of JAK inhibitors and immune cells in transplantation Publication date: June 2019 Source: Cytokine & Growth Factor Reviews, Volume 47 Author(s): Nicolas Sailliet, Carole Brosseau, Jean-Michel Robert, Sophie Brouard Abstract Immunosuppressive challenge after transplantation has dual objectives, namely, to efficiently inhibit immune populations involved in acute, chronic, humoral or cellular transplant rejection while minimizing the effect on immune integrity toward pathogens. The current immunosuppressive strategies show limited efficacy and remain associated with strong side effects, and thus, it is essential to develop new strategies. The use of Janus kinase (JAK) inhibitors is one of the new strategies focusing on cytokine pathways. Specifically, the first-generation JAK inhibitors (JAKis) showed low specificity toward the four known JAK molecules and did not exhibit better effects than calcineurin inhibitors, which constitute the standard treatment posttransplantation. However, because the new generation of JAKis present higher specificity, we are gaining further insights on the response of cells to these inhibitions. This review focuses on the impact of JAKis on different immune cell subsets, focusing on their role in transplantation.

TNFR2 signaling modulates immunity after allogeneic hematopoietic cell transplantation Publication date: June 2019 Source: Cytokine & Growth Factor Reviews, Volume 47 Author(s): Antonella Mancusi, Maite Alvarez, Sara Piccinelli, Andrea Velardi, Antonio Pierini Abstract Tumor necrosis factor-α (TNF-α) signaling through TNF receptor 2 (TNFR2) plays a complex immune regulatory role in allogeneic hematopoietic cell transplantation (HCT). TNF-α is rapidly released in the circulation after the conditioning regimen with chemotherapy and/or radiotherapy. It activates the function of donor alloreactive T cells and donor Natural Killer cells and promotes graft versus tumor effects. However, donor alloreactive T cells also attack host tissues and cause graft versus host disease (GVHD), a life-threatening complication of HCT. Indeed, anti-TNF-α therapy has been used to treat steroid-refractory GVHD. Recent studies have highlighted another role for TNFR2 signaling, as it enhances the function of immune cells with suppressive properties, in particular CD4+Foxp3+ regulatory T cells (Tregs). Various clinical trials are employing Treg-based treatments to prevent or treat GVHD. The present review will discuss the effects of TNFR2 signaling in the setting of allogeneic HCT, the implications for the use of anti-TNF-α therapy to treat GVHD and the clinical perspectives of strategies that specifically target this pathway.