From Acute Infection to Prolonged Health Consequences: Understanding Health Disparities and Economic Implications in Long COVID Worldwide.

The COVID-19 pandemic has resulted in a growing number of patients experiencing persistent symptoms and physiological changes after recovering from acute SARS-CoV-2 infection, known as Long COVID. Long COVID is characterized by recurring symptoms and inflammation across multiple organ systems. Diagnosis can be challenging, influenced by factors like demographics, comorbidities, and immune responses. Long COVID impacts various organ systems and can have neuropsychological effects. Health disparities, particularly related to race, contribute to a higher burden of infection and ongoing symptoms in minority populations. Managing Long COVID entails addressing a spectrum of symptoms that encompass physical, cognitive, and psychological aspects. The recovery period for patients with Long COVID can vary significantly, influenced by factors like the severity of the disease, hospitalization, comorbidities, and age. Currently, there are no universally effective treatments, although certain interventions show promise, necessitating further research. Self-management and rehabilitation programs can provide relief, but more research is needed to establish their effectiveness. Preventive measures such as vaccination and the use of antiviral medications and metformin. It is imperative to conduct further research to develop evidence-based guidelines and gain a better understanding of the long-term implications of COVID-19. Long COVID could have substantial economic impact on the labor market, productivity, healthcare expenditures, and overall economic growth. To address the challenges patients with long-term complications face, there is a focus on strategies like promoting telework and flexible work arrangements to accommodate diverse symptoms, particularly chronic fatigue and other Long COVID effects. In conclusion, this review emphasizes the multifaceted complexity of Long COVID and the ongoing need to address its potential long-term health and economic impacts.

Syntenin-1-mediated arthritogenicity is advanced by reprogramming RA metabolic macrophages and Th1 cells.

OBJECTIVES: Syntenin-1, a novel endogenous ligand, was discovered to be enriched in rheumatoid arthritis (RA) specimens compared with osteoarthritis synovial fluid and normal synovial tissue (ST). However, the cellular origin, immunoregulation and molecular mechanism of syntenin-1 are undescribed in RA. METHODS: RA patient myeloid and lymphoid cells, as well as preclinical models, were used to investigate the impact of syntenin-1/syndecan-1 on the inflammatory and metabolic landscape. RESULTS: Syntenin-1 and syndecan-1 (SDC-1) co-localise on RA ST macrophages (MΦs) and endothelial cells. Intriguingly, blood syntenin-1 and ST SDC-1 transcriptome are linked to cyclic citrullinated peptide, erythrocyte sedimentation rate, ST thickness and bone erosion. Metabolic CD14+CD86+GLUT1+MΦs reprogrammed by syntenin-1 exhibit a wide range of proinflammatory interferon transcription factors, monokines and glycolytic factors, along with reduced oxidative intermediates that are downregulated by blockade of SDC-1, glucose uptake and/or mTOR signalling. Inversely, IL-5R and PDZ1 inhibition are ineffective on RA MΦs-reprogrammed by syntenin-1. In syntenin-1-induced arthritis, F4/80+iNOS+RAPTOR+MΦs represent glycolytic RA MΦs, by amplifying the inflammatory and glycolytic networks. Those networks are abrogated in SDC-1-/- animals, while joint prorepair monokines are unaffected and the oxidative metabolites are moderately replenished. In RA cells and/or preclinical model, syntenin-1-induced arthritogenicity is dependent on mTOR-activated MΦ remodelling and its ability to cross-regulate Th1 cells via IL-12 and IL-18 induction. Moreover, RA and joint myeloid cells exposed to Syntenin-1 are primed to transform into osteoclasts via SDC-1 ligation and RANK, CTSK and NFATc1 transcriptional upregulation. CONCLUSION: The syntenin-1/SDC-1 pathway plays a critical role in the inflammatory and metabolic landscape of RA through glycolytic MΦ and Th1 cell cross-regulation (graphical abstract).

Inhibition of IRAK4 dysregulates SARS-CoV-2 spike protein-induced macrophage inflammatory and glycolytic reprogramming.

Escalated innate immunity plays a critical role in SARS-CoV-2 pathology; however, the molecular mechanism is incompletely understood. Thus, we aim to characterize the molecular mechanism by which SARS-CoV-2 Spike protein advances human macrophage (MÏ´) inflammatory and glycolytic phenotypes and uncover novel therapeutic strategies. We found that human MÏ´s exposed to Spike protein activate IRAK4 phosphorylation. Blockade of IRAK4 in Spike protein-stimulated MÏ´s nullifies signaling of IRAK4, AKT, and baseline p38 without affecting ERK and NF-κB activation. Intriguingly, IRAK4 inhibitor (IRAK4i) rescues the SARS-CoV-2-induced cytotoxic effect in ACE2+HEK 293 cells. Moreover, the inflammatory reprogramming of MÏ´s by Spike protein was blunted by IRAK4i through IRF5 and IRF7, along with the reduction of monokines, IL-6, IL-8, TNFα, and CCL2. Notably, in Spike protein-stimulated MÏ´s, suppression of the inflammatory markers by IRAK4i was coupled with the rebalancing of oxidative phosphorylation over metabolic activity. This metabolic adaptation promoted by IRAK4i in Spike protein-activated MÏ´s was shown to be in part through constraining PFKBF3, HIF1α, cMYC, LDHA, lactate expression, and reversal of citrate and succinate buildup. IRAK4 knockdown could comparably impair Spike protein-enhanced inflammatory and metabolic imprints in human MÏ´s as those treated with ACE2, TLR2, and TLR7 siRNA. Extending these results, in murine models, where human SARS-CoV-2 Spike protein was not recognized by mouse ACE2, TLRs were responsible for the inflammatory and glycolytic responses instigated by Spike protein and were dysregulated by IRAK4i therapy. In conclusion, IRAK4i may be a promising strategy for severe COVID-19 patients by counter-regulating ACE2 and TLR-mediated MÏ´ hyperactivation. IRAK4i therapy counteracts MÏ´ inflammatory and glycolytic reprogramming triggered by Spike protein. This study illustrates that SARS-CoV-2 Spike protein activates IRAK4 signaling via ACE2 as well as TLR2 and TLR7 sensing in human MÏ´s. Remarkably, IRAK4i treatment can dysregulate both ACE-dependent and independent (via TLR sensing) SARS-CoV-2 Spike protein-activated inflammatory and metabolic imprints.

Metabolic reprogramming of macrophages instigates CCL21-induced arthritis.

This study was designed to delineate the functional significance of CCL21 in metabolic reprogramming in experimental arthritis and differentiated rheumatoid arthritis (RA) macrophages (MΦs). To characterize the influence of CCL21 on immunometabolism, its mechanism of action was elucidated by dysregulating glucose uptake in preclinical arthritis and RA MΦs. In CCL21 arthritic joints, the glycolytic intermediates hypoxia-inducible factor 1α (HIF1α), cMYC and GLUT1 were overexpressed compared with oxidative regulators estrogen-related receptor γ and peroxisome proliferator-activated receptor gamma coactivator 1 (PGC1)-α. Interestingly, 2-deoxy-D-glucose (2-DG) therapy mitigated CCL21-induced arthritis by restraining the number of joint F4/80+ iNOS+ MΦs without impacting F4/80+ Arginase+ MΦs. Similar to the preclinical findings, blockade of glycolysis negated CCL21-polarized CD14+ CD86+ GLUT+ MΦ frequency; however, CD14+ CD206+ GLUT+ MΦs were not implicated in this process. In CCL21-induced arthritis and differentiated RA MΦs, the inflammatory imprint was uniquely intercepted by 2-DG via interleukin-6 (IL-6) downregulation. Despite the more expansive inflammatory response of CCL21 in the arthritic joints relative to the differentiated RA MΦs, 2-DG was ineffective in joint tumor necrosis factor-α, IL-1ß, CCL2 and CCL5 enrichment. By contrast, disruption of glycolysis markedly impaired CCL21-induced HIF1α and cMYC signaling in arthritic mice. Notably, in RA MΦs, glycolysis interception was directed toward dysregulating CCL21-enhanced HIF1α transcription. Nonetheless, in concurrence with the diminished IL-6 levels, CCL21 differentiation of CD14+ CD86+ GLUT1+ MΦs was reversed by glycolysis and HIIF1α inhibition. Moreover, in the CCL21 experimental arthritis or differentiated RA MΦs, the malfunctioning metabolic machinery was accompanied by impaired oxidative phosphorylation because of reduced PGC1α or peroxisome proliferator-activated receptor-γ expression. CCL21 reconfigures naïve myeloid cells into glycolytic RA CD14+ CD86+ GLUT+ IL-6high HIF1αhigh MΦs. Therefore, inhibiting the CCL21/CCR7 pathway may provide a promising therapeutic strategy.

IRAK4 inhibitor mitigates joint inflammation by rebalancing metabolism malfunction in RA macrophages and fibroblasts.

Recent studies show a connection between glycolysis and inflammatory response in rheumatoid arthritis (RA) macrophages (MΦs) and fibroblasts (FLS). Yet, it is unclear which pathways could be targeted to rebalance RA MΦs and FLS metabolic reprogramming. To identify novel targets that could normalize RA metabolic reprogramming, TLR7-mediated immunometabolism was characterized in RA MΦs, FLS and experimental arthritis. We uncovered that GLUT1, HIF1α, cMYC, LDHA and lactate were responsible for the TLR7-potentiated metabolic rewiring in RA MΦs and FLS, which was negated by IRAK4i. While in RA FLS, HK2 was uniquely expanded by TLR7 and negated by IRAK4i. Conversely, TLR7-driven hypermetabolism, non-oxidative PPP (CARKL) and oxidative phosphorylation (PPARγ) were narrowly dysregulated in TLR7-activated RA MΦs and FLS and was reversed by IRAK4i. Consistently, IRAK4i therapy disrupted arthritis mediated by miR-Let7b/TLR7 along with impairing a broad-range of glycolytic intermediates, GLUT1, HIF1α, cMYC, HK2, PFKFB3, PKM2, PDK1 and RAPTOR. Notably, inhibition of the mutually upregulated glycolytic metabolites, HIF1α and cMYC, was capable of mitigating TLR7-induced inflammatory imprint in RA MΦs and FLS. In keeping with IRAK4i, treatment with HIF1i and cMYCi intercepted TLR7-enhanced IRF5 and IRF7 in RA MΦs, distinct from RA FLS. Interestingly, in RA MΦs and FLS, IRAK4i counteracted TLR7-induced CARKL reduction in line with HIF1i. Whereas, cMYCi in concordance with IRAK4i, overturned oxidative phosphorylation via PPARγ in TLR7-activated RA MΦs and FLS. The blockade of IRAK4 and its interconnected intermediates can rebalance the metabolic malfunction by obstructing glycolytic and inflammatory phenotypes in RA MΦs and FLS.