Early Immune Response by Alveolar Epithelial Cells (ATII)
Activated alveolar macrophages (AM) and recruited inflammatory monocytes/macrophages are majorly responsible for the secretion of cytokines and chemokines in early phases of infection, with a substantial contribution from infected ATII cells as well. This early response is necessary to recruit and activate the adaptive immune system and hence drive the clearance of the virus without inflicting immunopathological state. While the levels of cytokines and chemokines are well-regulated during this phase of infection, a check on the activation profile and recruitment of these innate immune to the sites of infection is critical. Thus, a regulated and controlled release of cytokines and chemokines in the early phase of infection is not necessarily proinflammatory but drives the successful viral clearance and the probable reason behind the limited propagation of infection as seen in the majority of the COVID-19 cases exhibiting mild symptoms (Song et al., 2020; Tay et al., 2020).
Among the cytokines secreted by virus-infected airway epithelial cells, IL-6 plays a prominent role in the early recruitment and differentiation of monocytes, neutrophils, and lymphocytes which express the corresponding IL-6 receptor (IL-6R). Though IL-6 is chiefly secreted by macrophages (activated AMs and inflammatory macrophages) in the lungs, secretion of IL-6 by ATII is also significant. In vitro studies on SARS-CoV have shown the release of IL-6 by ATII in response to RIG-I and TLR signaling via activation of NF κB pathway (Ndlovu et al., 2009; Tanaka et al., 2012). Additionally, proinflammatory cytokines TNF-α and IL-1β secreted by macrophages act on ATII cells to cause the release of IL-6 (Crestani et al., 1994; Schwingshackl et al., 2013).
Transcriptional profiling in normal human bronchial epithelial (NHBE) infected with SARS-CoV-2 shows upregulation of IL-6, suggesting that these lung epithelial cells may contribute to early IL-6 response seen in non-severe COVID-19 patients (Blanco-Melo et al., 2020). However, more conclusive studies like tissue immunohistochemistry or single-cell immuno-profiling of the lung epithelial cells will clarify their contribution in IL-6 secretion in vivo.