Editorial: Unraveling the Molecular Mechanisms of Cytokine Signaling in Regulating Inflammatory Diseases

Jian Zheng ^1* Huawei Mao ^2* Wai Po Chong ^3*

• ¹ University of Louisville, Louisville, Colorado, United States
• ² Capital Medical University, Beijing, Beijing Municipality, China
• ³ School of Chinese Medicine, Hong Kong Baptist University, Hong Kong, China

Chronic and dysregulated inflammation is a hallmark of many autoimmune and inflammatory diseases, significantly impacting patient health and quality of life. Despite their prevalence, the intricate molecular mechanisms underlying cytokine regulation in these conditions remain poorly understood. This special issue aims to bridge this knowledge gap by exploring the complex network of cytokine signaling pathways and their roles in immunoregulation during inflammatory diseases. Through a collection of nine research articles and six review articles, we delve into the latest discoveries and insights, providing a comprehensive overview of the current state of research in this critical area.Cambon et. al. investigates the cytokine profiles in the lung compartment of COVID-19 patients, particularly those with acute respiratory distress syndrome (C-ARDS). They evaluated caspase-1 activation, IL-1 signature, and other inflammatory cytokine pathways using post-mortem lung tissues, bronchoalveolar lavage fluids (BALF), and serum. Their findings reveal elevated levels of proinflammatory molecules included caspase-1, IL-1β, IL-1Ra, IL-6, IFN-γ, and CXCL-10 in BALF from steroid-treated C-ARDS patients, highlighting the predominant IL-1β/IL-6 signature and IFNγ-associated chemokines despite steroid treatment. This study underscores the potential of targeting these pathways to improve treatment response and limit lung damage in ARDS.In another study, Vorobyeva DA et. al. developed an ex vivo model of SARS-CoV-2 lung infection to study cytokine production. Their findings reveal elevated concentrations of proinflammatory mediators, namely G-CSF, GM-CSF, GRO-a, IFN-γ, IL-6, IL-8, IP-10, MCP-3, MIP-1a, PDGF-AA, and VEGF in infected lung tissue, reflecting the cytokine alterations observed in COVID-19 patients. This model provides a valuable platform for investigating SARS-CoV-2 infection mechanisms and testing antiviral drugs.The study by Bédard-Matteau J. et. al. identifies IL-17F as a key cytokine associated with severe COVID-19. Elevated IL-17F levels were found in severe cases, promoting neutrophil adhesion to endothelial cells via ERK1/2 and p38 MAPK-dependent pathways. These findings highlight the potential of targeting IL-17F signaling to mitigate neutrophilic inflammation and immunothrombosis in severe COVID-19.Von Stemann et. al. examine the association of cytokine autoantibodies (c-aAb) with community-acquired pneumonia (CAP). They measured c-aAb targeting various cytokines in plasma samples from 665 CAP patients. The results indicate that high-titer type 1 IFN c-aAb are more prevalent in men with SARS-CoV-2 infection, while GM-CSF c-aAb are associated with asthma and bronchiectasis comorbidities in men. These findings suggest that c-aAb specificity, comorbidity, and sex influence clinical outcomes in CAP, providing insights for personalized treatment strategies.The research by Yang et. al. investigates the therapeutic potential of myeloid-derived growth factor (MYDGF) in primary Sjögren's syndrome (pSS). Using a mouse model, they demonstrated that MYDGF treatment alleviates pSS symptoms by increasing salivary flow rate, reducing lymphocyte infiltration, and promoting M2 macrophage polarization. The study identifies the suppression of the CX3CL1/CX3CR1 axis as a key mechanism, suggesting MYDGF as a promising therapeutic target for pSS.The research by Lee et. al. explores the role of pregnane X receptor (PXR) in particulate matter (PM)-induced inflammation in atopic dermatitis (AD). Their findings indicate that PXR activation reduces type 17 inflammation by inhibiting the NF-κB pathway, suggesting PXR as a therapeutic target for controlling PM-induced AD aggravation. In addition, Xu et. al. review the emerging roles of protease-activated receptor 2 (PAR2) in various skin conditions, including atopic dermatitis, psoriasis, vitiligo, and melasma. The review highlights PAR2's involvement in the cutaneous microenvironment and associated comorbidities, proposing it as a key target for therapeutic interventions.Ouyang and Dai employed Mendelian randomization to explore the causal relationships between systemic inflammatory cytokines and adhesive capsulitis (AC). Their findings establish causal associations between IP-10, RANTES, SDF-1α, TNF-α levels, and AC risk, oqering new avenues for understanding AC pathogenesis and developing clinical management strategies.Liu et. al. identify MCP-3 as a significant prognostic biomarker for severe fever with thrombocytopenia syndrome (SFTS). Elevated MCP-3 levels correlate with adverse outcomes, providing a valuable tool for predicting prognosis and understanding the cytokine-mediated pathogenesis of SFTS.The bibliometric review by Liu et. al. focus on leukocyte cell-derived chemotaxin-2 (LECT2). The study identifies liver diseases, systemic inflammatory diseases, and amyloidosis as current research focuses, highlighting LECT2's potential for clinical diagnosis and treatment.In another reviews by Guo et. al. explores the role of the CCL2/CCR2 signaling axis in inflammatory and fibrotic diseases. CCL2, a pivotal cytokine, binds to its receptor CCR2, modulating the recruitment and activation of immune cells and influencing fibrosis progression in various organs. The paper highlights recent advances in diagnosing and treating fibrotic diseases linked to this pathway and calls for further research to elucidate its clinical significance across diqerent organ systems.In their review, Xie et. al. discuss recent advances in asthma immunology, emphasizing the heterogeneity of immune processes and phenotypes. The paper explores the key cellular and molecular mediators involved in type 2-high and type 2-low asthma endotypes and reviews innovative biological and targeted therapies. Understanding the dynamic and complex immunopathology of asthma is crucial for developing personalized interventions.The study by Chen et. al. investigates the role of LTβR signaling in chemotherapy-induced mucosal damage. Their findings suggest that LIGHT produced by T cells activates LTβR-RelB signaling in intestinal epithelial cells, promoting mucosal repair and oqering insights into therapeutic strategies for chemotherapy-induced damage.The review by Zong et. al. explores the cytokine signaling pathways regulating Treg cells and their implications for autoimmune diseases, transplant rejection, and cancer. Understanding these pathways oqers potential for developing Treg-based immunotherapies to restore immune balance.Another review by Huang et. al. examines the bidirectional regulation of the TRPM2 channel in oxidative stress, inflammation, and ischemia-reperfusion (I/R) injury. The TRPM2 channel's role in exacerbating or protecting against cellular damage under diqerent conditions provides insights into potential therapeutic strategies for related diseases.This special issue highlights the critical role of cytokine regulation in chronic inflammatory and autoimmune diseases. By unraveling the molecular mechanisms underlying cytokine signaling pathways, we gain valuable insights into disease progression and identify potential therapeutic targets. This research contributes to the advancement of precision medicine and the development of novel treatments, ultimately improving patient outcomes in autoimmune and inflammatory diseases.