The Role of Toll-like Receptor-4 in Macrophage Imbalance in Lethal COVID-19 Lung Disease, and Its Correlation with Galectin-3

Abstract

To the current data, there have been 6,955,141 COVID-19-related deaths worldwide, reported to WHO. Toll-like receptors (TLRs) implicated in bacterial and virus sensing could be a crosstalk between activation of persistent innate-immune inflammation, and macrophage’s sub-population alterations, implicated in cytokine storm, macrophage over-activation syndrome, unresolved Acute Respiratory Disease Syndrome (ARDS), and death. The aim of this study is to demonstrate the association between Toll-like-receptor-4 (TLR-4)-induced inflammation and macrophage imbalance in the lung inflammatory infiltrate of lethal COVID-19 disease. Twenty-five cases of autopsy lung tissues were studied by digital pathology-based immunohistochemistry to evaluate expression levels of TLR-4 (CD 284), pan-macrophage marker CD68 (clone KP1), sub-population marker related to alveolar macrophage Galectin-3 (GAL-3) (clone 9C4), and myeloid derived CD163 (clone MRQ-26), respectively. SARS-CoV-2 viral persistence has been evaluated by in situ hybridation (ISH) method. This study showed TLR-4 up-regulation in a subgroup of patients, increased macrophage infiltration in both Spike-1(+) and Spike-1(−) lungs (p < 0.0001), and a macrophage shift with important down-regulation of GAL-3(+) alveolar macrophages associated with Spike-1 persistence (p < 0.05), in favor of CD163(+) myeloid derived monocyte-macrophages. Data show that TLR-4 expression induces a persistent activation of the inflammation, with inefficient resolution, and pathological macrophage shift, thus explaining one of the mechanisms of lethal COVID-19.

The Role of TLR-2 in Lethal COVID-19 Disease Involving Medullary and Resident Megakaryocites Up-Regulation in the Microthrombosis Mechanism

“…Platelets have many TLRs on their cell membrane, including TLR4. Binding of microorganism (virus, bacteria, fungi) to TLR4 induces platelets activation and release of their granule content (many factors involved in different processes) [18] In our previous study, we demonstrated upregulation of TLR4 in lethal SARS-Cov 2 disease [19].…”

“…Clinicopathological data of selected patients.The group of patients that constituited our study has already been presented in our previous paper, in which we have investigated the role of Toll-Like receptor-4 in macrophage imbalance in lethal COVID 19 lung disease [19]. The characteristics of this group are summarized in the table 1.…”

The Role of TLR-2 in Lethal COVID-19 Disease Involving Medullary and Resident Lung Megakaryocyte Up-Regulation in the Microthrombosis Mechanism

“…Further details were published in our recent publication, in which we studied the involvement of TLR-4 in macrophage imbalances in deadly COVID-19 lung illness [14]. The control cases used in this investigation are surgical lung histological preparations from COVID-19-negative individuals.…”