Modulation of ACE-2 mRNA by inflammatory cytokines in human thyroid cells: a pilot study

Abstract

Introduction Angiotensin-converting-enzyme-2 (ACE-2) was demonstrated to be the receptor for cellular entry of SARS-CoV-2. ACE-2 mRNA was identified in several human tissues and recently also in thyroid cells in vitro. Purpose Aim of the present study was to investigate the effect of pro-inflammatory cytokines on the ACE-2 mRNA levels in human thyroid cells in primary cultures. Methods Primary thyroid cell cultures were treated with IFN-γ and TNF-α alone or in combination for 24 h. ACE-2 mRNA levels were measured by RT-PCR. As a control, the levels of IFN-γ inducible chemokine (CXCL10) were measured in the respective cell culture supernatants. Results The mean levels of ACE-2 mRNA increased after treatment with IFN-γ and TNF-α in all the thyroid cell preparations, while the combination treatment did not consistently synergically increase ACE-2-mRNA. At difference, CXCL10 was consistently increased by IFN-γ and synergically further increased by the combination treatment with IFN-γ + TNF-α, with respect to IFN-γ alone. Conclusions The results of the present study show that IFN-γ and, to a lesser extent TNF-α consistently increase ACE-2 mRNA levels in NHT primary cultures. More interestingly, the combined stimulation (proven to be effective according to the synergic effect registered for CXCL10) produces different responses in terms of ACE-2 mRNA modulation. These results would suggest that elevated levels of pro-inflammatory cytokines could facilitate the entering of the virus in cells by further increasing ACE-2 expression and/or account for the different degree of severity of SARS-COV-2 infection. This hypothesis deserves to be confirmed by further specific studies.

COVID-19-Associated Subacute Thyroiditis: Evidence-Based Data From a Systematic Review

“…SAT is generally secondary to upper respiratory tract infections by several viruses (3,10); thus, SAT might represent a potential complication of SARS-CoV-2 infection. The fact that SARS-CoV-2 recognizes angiotensin-converting enzyme 2 (ACE-2) as its cellular entry receptor (44) and the recent demonstration of ACE-2 expression in follicular thyroid cells would further support this possibility (45)(46)(47).…”

Evaluation of the diagnostic features and clinical course of COVID-19 vaccine–associated subacute thyroiditis

“…Recent studies showed that the mRNA of angiotensin-converting enzyme 2 (ACE2) was expressed in thyroid follicular cells. Thus, it was hypothesized that direct entry of the pathogen into the cell may be effective in COVID-19-related SAT cases [12,45,46]. In addition, cross-reactivity, which occurs as a result of the similarity of virus spike proteins encoded in all COVID-19 vaccines, especially mRNA vaccines, with mammalian hexa and heptapeptides (e.g., TPO proteins), seems to be another effective mechanism [39,47].…”

Subacute thyroiditis during the COVID-19 pandemic: a prospective study

“…Thyroid damage can be directly related to viral cytotoxicity or an immune response mediated by molecular mimicry [ 4 , 13 , 36 ]. Thyroid exhibits high mRNA expression of ACE2 and TMPRSS2 [ 4 – 6 ]. In a study examining the reaction of human monoclonal antibodies to SARS-CoV-2 proteins with tissue antigens, high homology between immunogenic epitopes of SARS-CoV-2 to human proteins, including thyroid peroxidase (TPO), was reported [ 36 ].…”

“…SARS-CoV-2 uses human angiotensin converting enzyme 2 (ACE2) for cell entry and transmembrane serine protease 2 receptor (TMPRSS2) for S- protein priming [ 2 ]. ACE2 and TMPRSS2 are expressed not only in the upper and lower respiratory tract but also in tissues, like thyroid, exocrine pancreas, intestinal tract, heart, proximal renal tubules, adipocytes, Sertoli and Leydig cells [ 3 – 6 ]. Possible mechanisms of virus-related injury are direct viral action or indirect damage through inflammatory and immunological pathways.…”