key: cord-0744331-x5hl2o6l
authors: Gulbas, Izabela; Gajewski, Adrian; Gawrysiak, Mateusz; Szewczyk, Robert; Likońska, Aleksandra; Michlewska, Sylwia; Kowalski, Marek L.; Chałubiński, Maciej
title: IL‐33 prevents the enhancement of AP‐N, DPP4, and ACE2 expression induced by rhinovirus HRV16 in the human lung endothelium—potential implications for coronaviral airway infections
date: 2022-02-16
journal: Allergy
DOI: 10.1111/all.15251
sha: 5e2cd500e48ca78772efde688176254c0ef4c0ab
doc_id: 744331
cord_uid: x5hl2o6l

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To the Editor,

The lung vascular endothelium is a semi-permeable barrier that regulates the flow of nutrients, ions, cytokines, and immune cells between blood and lung tissues. Being a source of inflammatory mediators, it plays a crucial role in maintaining pulmonary homeostasis and in driving immune responses. 1 The main target for rhinoviruses (HRV) is the airway epithelium. However, we have recently shown that HRV16 may also infect the lung vascular endothelium via ICAM-1. 1 As the vascular endothelium may express coronaviral entry receptors, including aminopeptidase N (AP-N), dipeptidyl peptidase 4 (DPP4), and angiotensin-converting enzyme 2 (ACE2), it may possibly be infected by human coronavirus 229E (HCoV229E) and highly pathogenic MERS-CoV and SARS-CoV-2. 2 The latter one is responsible for currently ongoing COVID-19 pandemics. 3 Seasonal peaks for HRV infections occur in early fall (September-November) and spring (March-May), whereas low pathogenic HCoVs which evoke mostly mild upper airway infections appear in winter and early spring (December-April). Both viruses overlap in March and April. HRV and HCoV co-infections or subsequent infections may lead to severe viral pneumonias. In such patients, the diffuse alveolar lung damage and thrombotic angiopathy in alveolar capillaries have been observed, which suggests an active involvement of the lung vascular endothelium. 4 The effect of HRV on the expression of HCoV entry receptors on the lung vascular endothelium and its modulation by IL-33 widely distributed in asthmatic airways has not been elucidated. Recently, we have shown that IL-33 may enhance HRV-induced release of cytokines, chemokines, and growth factors by the lung vascular endothelium. 5 In order to analyze the effect of IL-33, HMVEC-L were pre-incubated with IL-33 (10 ng/ml) for 24 h and subsequently Figure S5A ,B,C).

Nevertheless, the increase of DPP4 and AP-N expression might be associated with autocrine action of other cytokines released by infected endothelium (i.e., IL-4,13; Figure S1D ,E). 6 This matter needs further elucidation. Mechanism of the inhibition of HRV16-induced AP-N, DPP4, and ACE2 expression by IL-33 appears to be more unclear, as we confirmed that IL-33 must affect cells prior to their exposure to the virus. When IL-33 was administered together with HRV16 at the same time, the inhibitory effect of IL-33 did not occur ( Figure S6 ).

In order to assess if HRV16 and IL-33 specifically regulate the to rhinovirus-related asthma exacerbations. 3 Finally, we intend to emphasize that these data refer to the lung vascular endothelium although the airway epithelium is a prime target for both HRV and

HCoV. However, the closeness of airway epithelium to endothelium lining mucosal vessels and alveolar capillaries enables the viral transmission between these tissues. Therefore, the possible modulation of coronavirus entry receptors by rhinovirus on the lung vascular endothelium and its clinical significance needs further research.

The authors declare no conflict of interest. 

Human rhinovirus HRV16 impairs barrier functions and regeneration of human lung vascular endothelium

SARS-CoV-2 infects endothelial cells in vivo and in vitro

The relationship between human coronaviruses, asthma and allergy-an unresolved dilemma

Coronavirus 229E with Rhinovirus co-infection causing severe acute respiratory distress syndrome with thrombotic microangiopathy and death during Covid-19 pandemic: lessons to be learnt

IL-33 augments the effect of rhinovirus HRV16 on inflammatory activity of human lung vascular endothelium-possible implications for rhinoviral asthma exacerbations

SARS-CoV-2 Receptor ACE2 is an interferon-stimulated gene in human airway epithelial cells and is detected in specific cell subsets across tissues