Type and Intensity as Key Variable of Exercise in Metainflammation diseases: A Review

Monocyte and lymphocyte subpopulations exhibit functions that vary between the anti- and pro-inflammatory spectrum, such as classic CD16- and non-classical CD16+ monocytes, as well as T helper 2 lymphocytes (Th2), the Th1/Th17 lymphocytes ratio, and T regulatory lymphocytes (Treg). Metabolic disease-associated inflammation is accompanied by an imbalance in monocyte and lymphocyte phenotypes and functionality, as well as a stronger proportion of inflammatory subpopulations. These changes appear to be important for the development and progression of diseases like diabetes and cardiovascular disease. On the other hand, the regular practice of physical exercise is an important tool to restore the functionality of monocytes and lymphocytes, and to balance the subtypes ratio. However, key variables regarding exercise prescription, such as the type of exercise, intensity, and volume differentially impact on the acute and chronic immune response in individuals diagnosed with meta inflammation diseases. Here, we discuss the impact of different physical exercise protocols, acutely and chronically, on monocytes and lymphocytes of individuals with metabolic disease-associated inflammation. In this review, we focus on the best effects of different exercise protocols to dose the “exercise pill” in different inflammatory status.

Significance of Interleukin (IL)-4 and IL-13 in Inflammatory Arthritis

Interleukin (IL)-4 and IL-13 belong to the T helper 2 (Th2) cytokine family, along with IL-3, IL-5, and IL-9. These cytokines are key mediators of allergic inflammation. They have important immunomodulatory activities and exert influence on a wide variety of immune cells, such as B cells, eosinophils, basophils, monocytes, fibroblasts, endothelial cells, airway epithelial cells, smooth muscle cells, and keratinocytes. Recent studies have implicated IL-4 and IL-13 in the development of various autoimmune diseases. Additionally, these cytokines have emerged as potential players in pathogenesis of inflammatory arthritis. Recent findings suggest that the IL-4 and IL-13 might play a significant role in the downregulation of inflammatory processes underlying RA pathology, and beneficially modulate the course of the disease. This review summarizes the biological features of the IL-4 and IL-13 and provides current knowledge regarding the role of these cytokines in inflammatory arthritis.

The Protective Role of Yin‐Yang 1 in Cardiac Injury and Remodeling After Myocardial Infarction

Background Exploring potential therapeutic target is of great significance for myocardial infarction (MI) and post‐MI heart failure. Transcription factor Yin‐Yang 1 (YY1) is an essential regulator of apoptosis and angiogenesis, but its role in MI is unclear. Methods and Results The expression of YY1 was assessed in the C57BL/6J mouse heart following MI. Overexpression or silencing of YY1 in the mouse heart was achieved by adeno‐associated virus 9 injection. The survival, cardiac function, and scar size, as well as the apoptosis, angiogenesis, cardiac fibrosis, T helper 2 lymphocyte cytokine production, and macrophage polarization were assessed. The effects of YY1 on Akt phosphorylation and vascular endothelial growth factor production were also investigated. The expression of YY1 in heart was significantly stimulated by MI. The survival rate, cardiac function, scar size, and left ventricular volume of mice were improved by YY1 overexpression but worsened by YY1 silencing. YY1 alleviated cardiac apoptosis and fibrosis, promoted angiogenesis, T helper 2 cytokine production, and M2 macrophage polarization in the post‐MI heart, it also enhanced the tube formation and migration ability of endothelial cells. Enhanced Akt phosphorylation, along with the increased vascular endothelial growth factor levels were observed in presence of YY1 overexpression. Conclusions YY1 ameliorates cardiac injury and remodeling after MI by repressing cardiomyocyte apoptosis and boosting angiogenesis, which might be ascribed to the enhancement of Akt phosphorylation and the subsequent vascular endothelial growth factor up‐regulation. Increased T helper 2 cytokine production and M2 macrophage polarization may also be involved in YY1’s cardioprotective effects. These findings supported YY1 as a potential target for therapeutic investigation of MI.

Epidermal Barrier Dysfunction in Atopic Dermatitis

Impaired skin barrier is one of the hallmarks of atopic dermatitis (AD), with abnormalities in the cornified envelope, lipid lamellae, tight junctions and cutaneous microbiome. These findings are also present in nonlesional skin of AD individuals, suggesting that epidermal barrier defects may be the initial step towards the development of AD and eventually other atopic diseases (atopic march). It is currently known that pathophysiology of AD involves an interplay between this dysfunctional skin barrier and a predominantly type 2 skewed innate and adaptive immune responses, which further disrupt the skin barrier through type 2 cytokines. In this setting, there is enhanced penetration of environmental and food allergens through a deficient barrier, leading to an increased susceptibility to sensitization. During the sensitization process, thymic stromal lymphopoietin (TSLP) polarizes skin dendritic cells to a T-helper 2 response, and TSLP seems to be a key cytokine in the sensitization of food allergy, allergic asthma and rhinitis. In this review, the authors describe the current knowledge of the pathophysiology of the epidermal barrier, its disruption in AD and how it may be involved in the development of atopic comorbidities and the role of barrier repair therapy on the prevention of the atopic march progression.

Interleukin-31 promotes fibrosis and T helper 2 polarization in systemic sclerosis

Systemic sclerosis (SSc) is a chronic multisystem disorder characterized by fibrosis and autoimmunity. Interleukin (IL)-31 has been implicated in fibrosis and T helper (Th) 2 immune responses, both of which are characteristics of SSc. The exact role of IL-31 in SSc pathogenesis is unclear. Here we show the overexpression of IL-31 and IL-31 receptor A (IL-31RA) in dermal fibroblasts (DFs) from SSc patients. We elucidate the dual role of IL-31 in SSc, where IL-31 directly promotes collagen production in DFs and indirectly enhances Th2 immune responses by increasing pro-Th2 cytokine expression in DFs. Furthermore, blockade of IL-31 with anti-IL-31RA antibody significantly ameliorates fibrosis and Th2 polarization in a mouse model of SSc. Therefore, in addition to defining IL-31 as a mediator of fibrosis and Th2 immune responses in SSc, our study provides a rationale for targeting the IL-31/IL-31RA axis in the treatment of SSc.

IgM regulates airway hyperresponsiveness via modulation of actin associated genes.

Allergic asthma is a disease driven by T helper 2 (Th2) cells, eosinophilia, airway hyperresponsiveness (AHR) and IgE-secreting B cells. Asthma is largely controlled by corticosteroids and β2 adregenic receptor agonists that target and relax airway smooth muscle (ASM). Immunoglobulin M (IgM) isotype secreted by naïve B cells is important for class switching but may have other undefined functions. We investigated the role of IgM in a house dust mite (HDM)-induced Th2 allergic asthma model by sensitising wild type (WT) and IgM-deficient (IgM-/-) mice with HDM. We validated our findings using CRISPR and single cell force cytometry in human ASM. We found IgM to be essential in AHR but not Th2 airway inflammation or eosinophilia. RNA sequencing of lung tissue suggested that IgM regulated AHR through modulating brain-specific angiogenesis inhibitor 1-associated protein 2-like protein 1 (Baiap2l1) and erythroid differentiation regulator 1 (Erdr1). Deletion of BAIAP2L1 and ERDR1 reduced human ASM contraction when stimulated with TNF-α. These are unprecedented findings and have implications in future treatment of asthma beyond current therapies.