Physiology of Midkine and Its Potential Pathophysiological Role in COVID-19

Abstract

SARS-CoV2 infection not only causes abnormal severe pneumonia but also induces other relevant pathophysiological effects on several tissues and organs. In this regard, the clinical complications observed in COVID-19 include acute coronary syndrome, pulmonary thromboembolism, myocarditis and, in the severe cases, the occurrence of disseminated intravascular coagulation. Literature on COVID-19 highlighted the central role of the Renin Angiotensin Aldosterone System in the determinism of SARS-CoV2 cellular internalization in the target tissues. Lung degeneration and respiratory distress appear to be dependent on the perturbance of physiological mechanisms, such as the uncontrolled release of pro-inflammatory cytokines, a dysregulation of the fibrinolytic coagulative cascade and the hyperactivation of immune effector cells. In this mini review, we address the physiology of Midkine, a growth factor able to bind heparin, and its pathophysiological potential role in COVID-19 determinism. Midkine increases in many inflammatory and autoimmune conditions and correlates with several dysfunctional immune-inflammatory responses that appear to show similarities with the pathophysiological elicited by SARS-CoV2. Midkine, together with its receptor, could facilitate the virus entry, fostering its accumulation and increasing its affinity with Ace2 receptor. We also focus on Netosis, a particular mechanism of pathogen clearance exerted by neutrophils, which under certain pathological condition becomes dysfunctional and can cause tissue damage. Moreover, we highlight the mechanism of autophagy that the new coronavirus could try to escape in order to replicate itself, as well as on pulmonary fibrosis induced by hypoxia and on the release of cytokines and mediators of inflammation, correlating the interplay between Midkine and SARS-CoV2.

Context-aware deconvolution of cell-cell communication with Tensor-cell2cell

“…Specifically, epithelial cells are highlighted as the main sender cells in factor 1 (Figure 4a), involving top ranked signals such as APP, MDK, MIF and CD99 (Figure 4b). These molecules were reported to be produced by epithelial cells 29–35 and participate in immune cell recruiting 31–33 , in response to mechanical stress in lungs 34 and regeneration of the alveolar barrier during viral infection 35 . Importantly, MDK can exacerbate leukocyte recruitment to sites of inflammation 36 , consistent with the immune response that Tensor-cell2cell deconvolved in severe COVID-19 patients 18,37–39 .…”

“…Specifically, epithelial cells are highlighted as the main sender cells in factor 1 (Figure 4a), involving top ranked signals such as APP, MDK, MIF and CD99 (Figure 4b). These molecules were reported to be produced by epithelial cells [29][30][31][32][33][34][35] and participate in immune cell recruiting [31][32][33] , in response to mechanical stress in lungs 34 and regeneration of the alveolar barrier during viral infection 35 .…”

Common Molecular Pathways Between Post-COVID19 Syndrome and Lung Fibrosis: A Scoping Review

“…Furthermore, NETs can induce the EMT in lung epithelial cells, thus further supporting NET role in fibrosis pathogenesis (Middleton et al, 2020;Pandolfi et al, 2021;d'Alessandro et al, 2022). So much so that anti-midkine monoclonal antibodies have been proposed as a new potential therapeutic strategies in COVID-19 (Sanino et al, 2020).…”

Serum midkine level might be a diagnostic tool for COVID19 disease in pregnancy: From the disease severity, hospitalization and disease progression respects

“…It has been indicated that overexpression of midkine is associated with several biological processes such as differentiation, proliferation, carcinogenesis, adhesion, migration of cells and survival and it was considered as a heparin-binding growth factor or a cytokine [2] , [3] . Related to these physiological pathways, midkine plays an important role in multiple pathological conditions including inflammation, cancer, injury, autoimmune diseases, and neurodegenerative diseases [1] , [2] , [3] , [4] .…”

“…Midkine was found to be a physiological mediator of renin angiotensin aldosterone system (RAAS) and it plays an important role in interaction between kidney and lung [9] . It has been shown that RAAS is one of the key factors for the regulation of the migration and proliferation of the smooth muscle cells, the production of extracellular matrix (ECM), the upregulation of the adhesion molecules expression, and the production of proinflammatory cytokines [4] .…”