Testicles, adipose organ and heart: A new axis in the management of SARS-CoV-2?

The SARS-CoV-2 pandemic has highlighted the need to investigate the physiopathological dynamics related to the virus-host interaction.

Male sex represents a risk factor; several studies [1], [2] showed that men had higher risk of developing severe illness and higher mortality. Obesity is another important risk factor [3], [4], as higher BMI was correlated with worse clinical course and increased mortality irrespective of age, diabetes or hypertension4. We can hypothesize that ACE2 expression, combined with adipose organ endocrine contribution, heart and testicles, may play an important role in inflammatory and immune balance. Androgens can modulate inflammation [5], [6]; soluble androgen receptor (AR) activation can positively regulate ACE2 expression2 and increase IL-6 transcription, activating in turn the expression of the AR gene creating a circuit of mutual STAT3-mediated amplification [7], [8]. AR can be considered an important co-factor in development of severe forms of illness and is the only promoter described for the transcription of TMPRSS2 gene [9], [10], [11], [12], expressed in several tissues [13].

Adipose tissue is considered an endocrine organ [14], [15] exerting an effect on immune system and inflammatory cascades, due to adipocytokines and production of TNF-α, IL-6 and chemokines [16]. Leptin levels are directly proportional to fat mass levels [17] and can exert pro-inflammatory effects through structural similarities with cytokines such as IL-6, GM-CSF or IL-12 [16]. Granulocytes, monocytes, macrophages and lymphocytes can also express leptin receptors [18], [19], [20], [21] activating other immune cells [22]. Leptin and STAT3 transcription factor-induced by tyrosine phosphorylation has been observed in endothelial cells of human umbilical veins [23]. Should these data be confirmed as general mechanism, this may overlap with the IL-6 associated AR activation in other cellular lines, potentially turning on and feeding the previously described self-alimenting circuit. Also, long-term high-fat diet in mouse reduces ACE2 activity in adipose tissue due to increased expression of ADAM17, a protease responsible for ACE2 shedding, inducing elevation of angiotensin II levels, vasoconstriction, enhanced inflammation and thrombosis [24]. This effect could be enhanced by ACE2 down-regulation induced by viral invasion [25], thus being especially detrimental in people with baseline ACE2 dysregulation as in obesity.

Furthermore, preclinical evidence in vitro (cardiomyocytes) and in vivo (rodents) show that cardiac natriuretic peptides production could be downregulated by nutrients such as glucose and hormones such as leptin, which levels are elevated in obesity, as noted. These observations introduced the “natriuretic handicap“ concept and several studies confirmed these findings in obese humans [26], [27]. Considering natriuretic peptide system involvement either in inflammation regulation, as Atrial natriuretic peptide (ANP) reduces production of the proinflammatory cytokine TNF-α through NPR-A signalling pathway and consequent reduction of proinflammatory transcription factors NF-κB [28], is tempting to speculate that natriuretic handicap could contribute to an excessive immune response. Understanding relationships between these mechanisms could promote development of new therapeutic solutions in a perspective of tailored medicine, deserving further studies.

Declaration of Competing Interest

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.