In 2012, a group of researchers reported the discovery of irisin, a previously uncharacterized hormone derived from the transmembrane protein fibronectin type III domain-containing protein 5 (FNDC5), which is widely expressed in numerous tissues (1). Based on the functional characterization of irisin, it may be defined as a myokine (1) and an adipokine released during exercise (2). Further research has found that irisin mediates the conversion of white adipose tissue to brown adipose tissue, resulting in a thermogenic effect (1). In addition, irisin improves glucose and lipid metabolism (3–5) and ameliorates the effects of obesity-driven inflammation, metabolic syndrome, and diabetes (6–8). As a result, several beneficial effects on human health derived from exercise, such as reduced inflammation in pathological states, may be ascribed in part to irisin secretion (9, 10). Given these positive effects of exercise-induced irisin, it may play a role in mitigating the effects of other conditions that trigger systemic inflammation.

Coronavirus disease 2019 (COVID-19) is a highly infectious disease caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV2), which has reached alarming proportions during the pandemic (11). Its pathological features include exacerbated inflammation and induction of a cytokine storm, which contribute to the development of severe immune reactions (12–14). Therefore, one of the main therapeutic strategies targets the hyperactivation of immune responses (12). Multiple studies hypothesize exercise to be a protective factor against COVID-19 through the downregulation of the cytokine storm and reduction of sequelae (15, 16). It can also mitigate the progress of the infection, improve immune response and even work as a coadjutant therapy for COVID-19 (17). In this way, one observational study was able to associate moderate levels of exercise with a lower prevalence of COVID-19-related hospitalization (18). However, the role of irisin as a potential mechanism mediating exercise’s benefits in COVID-19 outcomes has yet to be uncovered.

In this review, we aim to discuss the anti-inflammatory effects of irisin, focusing on the MAPK, AMPK, and TLR4/MyD88 intracellular pathways, and examine how exercise-induced irisin may improve the outcomes of inflammatory conditions, such as COVID-19.

Irisin has 112 amino acid residues and is a proteolytic cleavage subproduct of the FNDC5 protein (1). FNDC5 is a type 1 membrane protein that contains 209 amino acids in mice and 212 in humans⁠. The FNDC5 precursor has five domains: the signal sequence (29 aa), fibronectin type III (94 aa), functionally unidentified region (28 aa), transmembrane (19 aa), and cytoplasmic (39 aa) domains. The N-terminal signal sequence is located in the extracellular environment, and the cytoplasmic domain is located at the C-terminus (1, 19, 20).

⁠Irisin has a very similar structure to fibronectin type III (FNIII) domains: a β-sandwich domain with four β-strands on one side and three on the other (19). However, irisin forms continuous antiparallel eight-stranded β-sheet dimers, a feature rarely found in other FNIII domains. Thus, irisin dimerization is associated with structural stability, receptor binding, and triggering signaling cascades (19).⁠

In rodents, irisin was identified in different tissues: muscle, lung, liver pancreas, adrenal glands, kidneys, and even in the central nervous system (21, 22). In humans, FNDC5 is predominantly expressed in muscle tissue, and its expression patterns establish a few primary predictors of circulating irisin, such as muscle mass and age (23). Therefore, increased muscle tissue due to a resistance training program could be a way to increase circulating irisin levels, and these observations are substantiated by studies showing an increase in circulating irisin levels after aerobic and resistance exercise sessions (24, 25). Furthermore, lower circulating irisin levels in older people have been noted because human muscle tissue mass decreases annually after 50 years of age (26).

Because older adults (> 60 years old) have lower physiological irisin levels, their circulating irisin levels tend to increase at a higher rate than in younger adults after training sessions, with a higher increase noted after intense training (24). Although exercise frequency is positively associated with increased irisin blood levels (25) populations that frequently exercise did not receive equal benefits from training interventions (23, 24). Thus, further research is necessary to understand the relationship between exercise and circulating irisin levels in trained and untrained populations. Interestingly, participants with a greater body mass index were less influenced by the acute irisin response due to exercise, a condition termed “irisin resistance syndrome” (25). Therefore, subjects who showed lower body mass index (BMI) levels throughout the intervention also experienced notable increases in circulating irisin levels (24).

Both irisin and its precursor are N-glycosylated proteins (1)⁠. In FNDC5, two asparagines (Asn36 and Asn81) were identified as the glycosylation sites. The modification is associated with critical functions such as cellular stability and localization of FNDC5. In addition, glycosylation increases the half-life and membrane incorporation of the protein. In contrast, unglycosylated FNDC5 has a shorter half-life and is abundantly retained in the endoplasmic reticulum (27)⁠.

Irisin has two additional potentially glycosylated asparagine residues (Asn7 and Asn52). Glycosylation may stimulate irisin secretion because FNDC5 membrane incorporation depends on it. In addition, adipose tissue browning is intensified with glycosylated irisin, and glycosylation does not impact irisin dimerization (19, 27, 28).

The mechanisms associated with FNDC5 cleavage into irisin and its release are still uncertain, but a disintegrin and metalloproteinase (ADAM) family member are purportedly involved. ADAM family inhibitors caused irisin levels to decrease, even though FNDC5 expression did not change (29). The first characterized binding partners for irisin were found in adipocytes and osteocytes, and irisin was identified as a potential modulator of bone metabolism (30). In binding assays, integrins such as αV/β5, and to a lesser extent α1/β1, possess a high affinity for irisin. Furthermore, the expression of integrin-like signaling mediators increased with irisin stimulation. Conversely, irisin signaling decreased with the use of integrin inhibitors. Thus, the proposed receptors for irisin in tissues are the αV-integrin family of proteins (30, 31)⁠.

Irisin may act through an alternative pathway in the lungs of mice with ischemia/reperfusion-induced injury. Irisin may enter injured cells, protecting them by targeting the mitochondrial uncoupling protein 2 (UCP2), reducing cellular oxidative stress. Remarkably, this effect appears to be mediated by lipid raft endocytosis of irisin from the bloodstream, indicating that irisin may act regardless of the presence of the receptor (32).

FNDC5 and irisin expression are regulated by the transcriptional coactivator peroxisome proliferator-activated receptor-gamma coactivator 1 alpha (PGC1-α). An increase in PGC1-α expression in the muscle of transgenic mice is associated with the browning of white adipose tissue (WAT) in a process mediated by irisin (1). Additionally, PGC1-α is associated with exercise-mediated benefits and energy metabolism, leading to the hypothesis that exercise may stimulate irisin release (1)

PGC1-α interacts with several transcription factors to regulate FNDC5 synthesis during exercise. In particular, the transcription factors estrogen-related receptor alpha (ERRα) and cAMP response element-binding protein (CREB) are two presumed PGC1-α partners that increase FNDC5 synthesis (33, 34)⁠. Furthermore, nuclear hormone receptors such as glucocorticoid receptor (GR), constitutive androstane receptor (CAR), and farnesoid X receptor (FXR) also increase FNDC5 mRNA levels in cell cultures. Notably, cortisol can modulate FNDC5/irisin transcription in some human hepatoma cell lines (35–37).⁠ Because cortisol suppresses inflammation, we asked whether irisin could function alongside cortisol as an anti-inflammatory myokine in response to high-intensity exercise or inflammation.

Further, mothers against decapentaplegic homolog 3 (SMAD3) reduced FNDC5/irisin and PGC1-α expression because SMAD3 ablated mice showed increased serum irisin and high PGC1-α and FNDC5 expression in muscle. Additionally, TGF-β signaling activates SMAD3 signaling and blocks FNDC5 and PGC1-α transcription (38)⁠.

In 2020, the world witnessed the rise of a new infectious disease caused by viral pneumonia, named COVID-19. Disease outbreaks began in 2019 in Wuhan, China, and spread to other countries and continents (39). As a result, the World Health Organization declared the disease a public health emergency in January 2020 and a pandemic in March 2020. As the pandemic progressed, over 400 million cases of COVID-19 and over 5.5 million deaths have been reported worldwide (11). Although a few infected individuals remain healthy and asymptomatic, the clinical spectrum of COVID-19 varies greatly, with increasing severity found in groups presenting comorbidities, including obesity, hypertension, diabetes, cardiovascular diseases, and old age (40, 41). The main clinical symptoms include fever, cough, respiratory distress/pneumonia, headache, anosmia, and ageusia, although atypical symptoms may also occur (39, 42).

SARS-CoV-2 causes the COVID-19 (42–44). It is a single-stranded RNA virus capable of infecting humans and other mammals, and it promotes disease due to the virus’s features and interaction with the host’s immune system (45). The interaction of the viral capsid protein S (spike protein) and human receptor proteins, mainly ACE-2 (angiotensin-converting enzyme 2) and TMPRSS2 (transmembrane protease, serine 2) enable virus entry into host cells (46). Indeed, ACE-2 levels are correlated with SARS-CoV-2 invasiveness potential and tropism in specific tissues. Tissues and organs expressing ACE-2, such as the lungs, heart, adipose tissue, and gastrointestinal tract, are the preferred targets for viral invasion (39, 47).

After viral uptake and fusion, its genetic material is uncoated and expressed, resulting in viral life cycle progression and replication (46). In the replication state, few or no symptoms are prevalent because tissue damage and immune responses are minimal, whereas organ damage and increasing severity of symptoms may occur as the infection progresses (14, 48). With immune cell recruitment, cytokine production begins to occur during immune response exacerbation. The expression of several types of cytokines may be increased in patients with COVID-19, such as IL1β, IL1RA, IL6, IL7, IL8, IL9, IL10, IFNγ, and TNFα (49, 50). Hence, one of the hallmarks of COVID-19 pathophysiology, hyperimmune activation, leads to a cytokine storm that is directly linked to disease severity (51). Although considerable research has been done, the COVID-19 literature evolves with new data released, and further research will continue while the pandemic persists.

Figure 1 briefly summarizes the inflammatory pathways that irisin may modulate during SARS-CoV2 infection, while Table 1 assembles the different effects of COVID-19, irisin, exercise, and sedentarism/aging over the inflammatory pathways discussed in this paper. In the first stage of the disease, SARS-CoV2 stimulates an innate immune response mediated specifically by macrophages, through pathogen-associated molecular patterns associated with TLR3, TLR7, and TLR8. In addition, the SARS-CoV-2 spike glycoprotein binds and activates TLR4 (3). Irisin can reduce TLR3 and TLR4 expression and possibly alleviates the innate immune response in the first stage of the disease, inhibiting the release of proinflammatory cytokines ( Figure 1A ) (29, 86).

In the second stage, the viral infection may result in a cytokine release storm that produces severe systemic inflammation. Increased cytokine levels activate tyrosine kinase receptors in macrophages, inducing MAPK pathway activation (67). In addition, severe systemic inflammation causes organ damage, inducing the production of DAMPs, which further activates the TLR4/MyD88 pathway (88, 90). Both the TLR4/MyD88 and MAPK pathways stimulate NF-kB, inducing an increase in the production of proinflammatory cytokines ( Figure 1B ) (13). Irisin has several modulation targets, including TLR4, MyD88, MAPK, and NF-κB. By reducing their expression levels, irisin reduces proinflammatory cytokine production ( Figure 1B ) (68). In addition, patients with COVID-19 may develop a bacterial coinfection that releases LPS and activates the TLR4/MyD88 pathway (112). Irisin causes a decrease in TLR4 and MyD88 levels, which could prevent the development of sepsis ( Figure 1B ).

Exercise increases energy expenditure and AMP levels, activates AMPK, and suppresses the mTOR pathway (54). On the other hand, sedentarism and aging may have the opposite effects, with a decrease in AMPK activation observed, whereas mTOR activation and proinflammatory cytokine production are induced ( Figure 1C ). Thus, irisin modulation is of particular interest as it counteracts the suppression of the AMPK pathway. In addition, irisin may also ameliorate the proinflammatory state by reducing mTOR and NF-κB activation ( Figure 1C ) (29, 59).

Even though irisin levels may vary following muscle mass, age, and involvement in physical activities, healthy and active people would benefit from irisin’s counterbalance mechanism, considering they would at least present physiological levels. For instance, obese, elderly, and sedentary subjects present loss of muscle mass and consequently lower irisin levels. These groups present a higher risk of developing COVID-19, with a lack of inflammatory counterbalance mechanism. Thus we suggest a potential role of irisin in preventing COVID-19 complications.

One limitation of the present work is that exercise, irisin, and inflammatory status are unveiled. Therefore, further studies have to be made to fulfill the gap in the current knowledge in the field. Furthermore, despite data on irisin and inflammation, COVID-19, and inflammation, the relations between irisin and COVID-19 are still poor. Furthermore, the knowledge about COVID-19 pathophysiology continues to evolve concerning the differences between current and future variants. So further studies will help to understand the role of irisin on COVID-19 outcome. Therefore, this review highlights the potential relation between irisin, inflammation, and COVID-19.

Together, increased irisin levels may counteract the adverse effects of COVID-19 during the various disease stages. Therefore, we hypothesized that irisin could prevent excessive inflammation, perhaps decreasing organ damage and dysfunction and secondary bacterial infection during hospitalization. Irisin’s anti-inflammatory modulation properties may also explain, at least in part, why healthy patients generally have a better prognosis for SARS-CoV2 infection. Further research is needed to understand the role of irisin on COVID-19 patients and may help develop new prevention and treatment strategies.

Conceptualization, writing—original draft preparation and editing, and funding acquisition: HA, GL, CF, Gd-A and PB. Final approval: PB and CG. All authors have read and agreed to the published version of the manuscript. All authors contributed to the article and approved the submitted version.

This work was supported by grants from Universidade Federal Fluminense (PROPPI/UFF), Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES) Grant [001], Programa de Biotecnologia da Universidade Federal Fluminense (UFF), Programa de Pós Graduação em Biologia Molecular Celular (UNIRIO), Universidade Federal do Estado do Rio de Janeiro (UNIRIO), Fundação Carlos Chagas Filho de Amparo à Pesquisa do Estado do Rio de Janeiro (FAPERJ) Grants [E-26/010.000983/2019, E-26/203.290/2017, and E-26/2010.592/2019, E-26/201.448/2021], Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq), and Instituto Oswaldo Cruz, FIOCRUZ. We also acknowledge financial support by the European Community’s Seventh Framework Programme (FP7-2007-2013) under grant agreement [HEALTH-F4-2011-282095] (TARKINAID).

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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