Editorial: Smoldering Inflammation in Cardio-Immune-Metabolic Disorders

Department of Translational Medical Sciences, University of Naples Federico II, Naples, Italy, Center for Basic and Clinical Immunology Research (CISI), University of Naples Federico II, Naples, Italy, 3 Institute of Experimental Endocrinology and Oncology (IEOS), National Research Council, Naples, Italy, Division of Cardiology, Department of Medicine, Johns Hopkins School of Medicine, Baltimore, MD, United States, Department of Biomedical Sciences, University of Padova, Padova, Italy, Centre for Experimental Medicine and Rheumatology, William Harvey Research Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, United Kingdom, 7 Istituti Clinici Scientifici Maugeri SpA

This Research Topic's driving force was to collect new acquisitions on the role of smoldering inflammation in diverse clinical pathological settings, examining them through the lens of temporal and spatial changes in immune cells and their products, such as cytokines.
Pucino et al. highlighted the interplay between metabolism, immunity and inflammation in patients with rheumatoid arthritis. The authors provided evidence that metabolic alterations of tissue microenvironment plays a pivotal role in the pathophysiology of rheumatoid arthritis. On the same ground, Moschetta et al. illustrated the role of inflammatory sinovitis in the development of hemophilic arthropathy. They discussed the role of imbalance of pro-and anti-inflammatory cytokines in inducing hemophilic arthropathy. The authors suggested that modulation of synovial inflammation could represent a novel therapeutic approach to prevent hemophilic arthropathy. Calcaterra et al. discussed the "two hits" hypothesis of synovitis in hemophilic arthropathy.
Rivellese et al. evaluated the possible contribution of synovial mast cells and their mediators to histological features of synovitis in severe and/or early rheumatoid arthritis. The authors demonstrated that disease-modifying anti-rheumatic drugs (DMARDs) reduced synovial inflammation and mast cell infiltration only in half of the patients examined. The presence of mast cells after 6 months of treatment with DMARDs was associated with a higher disease activity. They concluded that synovial mast cell are associated with disease severity. Gisondi et al. discussed the pathophysiological relationship between psoriasis, a chronic, systemic immune-mediated disease and cardiometabolic comorbidities and the therapeutic strategies to modulate low-grade inflammation in these patients.
However, severe eosinophilic asthma may be resistant to glucocorticoids and require therapies with specific monoclonal antibodies (mAbs), targeting IL-5/IL-5Rα . Experimental models and clinical studies have demonstrated that IL-13 is an important cytokine in chronic airway inflammation. IL-13 is produced by human basophils (Gibbs et al., 1996;Ochensberger et al., 1996;Redrup et al., 1998;Patella et al., 2000;Genovese et al., 2003;Galeotti (Fushimi et al., 1998;Lorentz et al., 2000), the primary effector cells of allergic disorders (Marone et al., 2014;Varricchi et al., 2019c;Miyake et al., 2020). Marone et al. analyzed the biochemical and immunological effects of IL-13 in the context of experimental models of asthma and in asthmatic subjects. Despite promising results in several in vitro and in vivo models of allergic inflammation, the efficacy of mAbs anti-IL-13 in patients with asthma has been surprisingly negative (Hanania et al., 2016;Russell et al., 2018).
Obesity is one of the major health burdens of the twentyfirst century as it contributes to insulin resistance and type 2 diabetes (Calay and Hotamisligil, 2013). Chronic, low-grade inflammation in adipose tissue is a crucial risk factor for the development of obesity and type 2 diabetes. Obesity is characterized by activation of the innate and adaptive immune system which may explain the increase susceptibility to develop metabolic disorders such as diabetes mellitus (Saltiel and Olefsky, 2017). Zatterale et al. carefully examined the molecular pathways linking obesity-induced inflammation and insulin resistance. The authors elegantly discussed the complex role of innate and adaptive immunity in obesity. Finally, they provided evidence that low-grade inflammation might represent a novel therapeutic target for metabolic diseases. Osteopontin produced by several immune cells, endothelial cells, and fibroblasts, is involved in cardiovascular diseases (Abdelaziz Mohamed et al., 2019;Vianello et al., 2020). Moschetta et al. reported that osteopontin is linked to pathological dysregulation of the arginine pathway in patients with coronary artery disease.
Alzheimer's disease (AD) is the most prevalent form of dementia in the elderly. A vast amount of literature indicates a role of inflammation in AD pathophysiology and several findings support the existence of a link between periodontitis, a chronic inflammatory oral disease and Alzheimer's disease (Heppner et al., 2015). Liccardo et al. provided an upgrade on the emerging evidence supporting a relationship between periodontitis and Alzheimer's disease.
But how do we protect ourselves from chronic inflammation? The above contributions highlight the need to counter clinical conditions that can determine the progression from acute to chronic inflammation. Among them, we should aim to lower cholesterol, reduce obesity, prevent gum disease, and stop smoking. Dietary changes are also likely to be important, including eliminating food and beverages high in fructose and other refined sugars while increasing our intake of polyphenols (Serino and Salazar, 2018), such as those contained in vegetables, fruits, and seeds. These alterations may represent an 'antiinflammatory' lifestyle which may help reduce smoldering inflammation in chronic inflammatory conditions. Is this doable? In other words, does the multisource smoldering inflammation require many remedies? If so, then there might be no cure for this condition, and we have to side with Chekov on this one. In this scenario appears important to mention that results from the CANTOS trial have demonstrated that treatment with Canakinumab, a monoclonal antibody anti-IL-1β of patients with previous myocardial infarction and a high-sensitivity C-reactive protein level results in significantly reduced cardiovascular events. Moreover, patients with genetically-determined decreased IL-6 signaling showed a reduced risk of cardiovascular events and increased life-span (Rosa et al., 2019).
Early interventions, however, would help (e.g., a timely detection of any inflammatory focus). Pursuing this is feasible for easy-to-access areas of our body, such as skin, joints, and mouth. Moreover, preventing or eradicating the accumulation of visceral fat that is a consolidated fomite of chronic inflammation and atherosclerosis (Alexopoulos et al., 2014). Conversely, doing so for visceral organs is more complicated and requires a more articulated level of repeated inspections.
If chronic inflammation is, indeed, an enduring burning flame, then making an analogy to the fire of a match suggests another ineludible point (Figure 1). A match is composed of fuel (more specifically, antimony trisulfide) and an oxidant (an oxygen provider, i.e., potassium chlorate). We have described "antimony trisulfide" of different kinds (triggers and fuels), but we should not forget the importance of countering oxidative stress while cutting off the fuel and the trigger. Indeed, along with cytokines, reactive oxygen species can act as propagators of smoldering inflammation (Liu et al., 2020;Wiegman et al., 2020), morphing the phenomenon from local to systemic. We feel that this is another fertile and yet poorly explored terrain for future investigation.
We hope that articles harnessed in the current Research Topic help the readers with some new clues on how low-grade inflammation is initiated, maintained, and eventually resolved, at least to some extent.

AUTHOR CONTRIBUTIONS
GV wrote the article. NP, FR, and GR edited the article. GV, NP, and GR revised the article. All authors contributed to the article and approved the submitted version.

FUNDING
This manuscript was supported in part by grants from Regione Campania CISI-Lab Project, CreME Project, TIMING Project, Campania Bioscience to GV. NP was funded by NIH (R01 HL136918).