IL-4/IL-13 remodeling pathway of COVID-19 lung injury

Abstract

The COVID-19 fatality rate is high when compared to the H1N1pdm09 (pandemic Influenza A virus H1N1 subtype) rate, and although both cause an aggravated inflammatory response, the differences in the mechanisms of both pandemic pneumonias need clarification. Thus, our goal was to analyze tissue expression of interleukins 4, 13, (IL-4, IL-13), transforming growth factor-beta (TGF-β), and the number of M2 macrophages (Sphingosine-1) in patients who died by COVID-19, comparing with cases of severe pneumopathy caused by H1N1pdm09, and a control group without lung injury. Six lung biopsy samples of patients who died of SARS-CoV-2 (COVID-19 group) were used and compared with ten lung samples of adults who died from a severe infection of H1N1pdm09 (H1N1 group) and eleven samples of patients who died from different causes without lung injury (CONTROL group). The expression of IL-4, IL-13, TGF-β, and M2 macrophages score (Sphingosine-1) were identified through immunohistochemistry (IHC). Significantly higher IL-4 tissue expression and Sphingosine-1 in M2 macrophages were observed in the COVID-19 group compared to both the H1N1 and the CONTROL groups. A different mechanism of diffuse alveolar damage (DAD) in SARS-CoV-2 compared to H1N1pdm09 infections were observed. IL-4 expression and lung remodeling are phenomena observed in both SARS-CoV-2 and H1N1pdm09. However, SARS-CoV-2 seems to promote lung damage through different mechanisms, such as the scarce participation Th1/Th17 response and the higher participation of the Th2. Understanding and managing the aggravated and ineffective immune response elicited by SARS-CoV-2 merits further clarification to improve treatments propose.

Lung Neutrophilic Recruitment and IL-8/IL-17A Tissue Expression in COVID-19

“…Corroborating with other authors, and based on our results, SARS-CoV-2 appeared to promote injury by different mechanisms, evading an adaptive Th1 response and inducing a Th2 response, ineffective against viral agents ( 21 , 40 – 44 ). In contrast, H1N1pmd09 demonstrated an intense innate response Th1/Th17, responsible for severe lung injury mediated by increased neutrophils recruitment.…”

“…This process is mediated by the angiotensin-converting enzyme 2 (ACE-2) in lung tissue (6,7), but how this damage starts and compromises the lung tissue needs to be better investigated. Diffuse alveolar damage is associated with a host defense response regulated by a complex interaction of cytokines and inflammatory cells trigger by macrophages activation that can recruit circulating neutrophils, amplifying the response (8)(9)(10)(11)(12).…”

Blood Interferon-α Levels and Severity, Outcomes, and Inflammatory Profiles in Hospitalized COVID-19 Patients

“…The role of T2-cytokine in the context of COVID-19 is still largely unknown. A very recent study showed overexpression of Th2 cytokine in the lung of COVID-19 patients and proposed a role for Th2 cytokine in promoting lung damages in the context of COVID-19 ( 27 ). Not lastly, a negative interplay has been previously documented between Th2 inflammatory milieu and interferon responses ( 28 ).…”

ACE2-lentiviral transduction enables mouse SARS-CoV-2 infection and mapping of receptor interactions

“…IPA USR analyses of the 551 DEGs showed a clear reduction in inflammatory cytokine annotations, although the IL4 signature remained a dominant feature on day 6 (Figure 4C, Supplementary Table 2D-E). A Th2 skew and IL-4 have both been associated with lung damage in COVID-19 patients (Vaz de Paula et al, 2020). On day 6 there was an up-regulation of USRs primarily associated with tissue repair (Figure 4D, Supplementary Table 2F); MAPK1 (also known as ERK) and MAPK9 (Lavoie et al, 2020), BMP7 (Sountoulidis et al, 2012), TCF7L2 (Zhu et al, 2015), and KLF4 (Lin et al, 2017; Raslan and Yoon, 2020).…”

“…The lentivirus-hACE2 C57BL/6J mouse model of SARS-CoV-2 infection shares many cytokine signatures with those seen in human COVID-19 patients; IL-2, IL-10, IL-6, TNFα, IL-4, IL-1β, IFNγ and CSF3 signatures were found in SARS-CoV2-infected lentivirus-hACE2 transduced C57BL/6J mice on day 2 post infection, and elevated levels of these cytokines are found in COVID-19 patients (Han et al, 2020; Huang et al, 2020). Several of these cytokines have been implicated as mediators of COVID-19; for instance, IL-6 (Herold et al, 2020; Masiá et al, 2020; Xia et al, 2020), IL-4 (Vaz de Paula et al, 2020), IL-10 (Lu et al, 2021) and IFNγ (Gadotti et al, 2020). On day 6 post infection the lentivirus-hACE2 C57BL/6J mouse model showed a series of signatures associated with tissue repair.…”