A new therapeutic approach against kidney damage in LN and COVID-19

Lupus nephritis (LN) and coronavirus disease 2019 (COVID-19) both display myeloid cell dysfunction which can lead to altered signaling resulting in tissue damage, such as kidney injury. Up to 50% of LN patients develop chronic kidney disease (CKD) and 25% of COVID-19 patients are reported to experience acute kidney injury (AKI) leading to long-term injury and loss of function (42,43,63). Myeloid cell dysfunction leads to secretion of proinflammatory cytokines (IL-6, IL-1b, TNF-a) which have been shown to promote kidney damage by stimulating immune cell infiltration and cell death (60-62). Both diseases have notable increase in circulating soluble urokinase plasminogen activating receptor (suPAR), which have been attributed to both AKI and CKD (39,54,55). While dysfunction has been noted in COVID-19, there is no conclusive evidence on whether this disease and organ injury is myeloid cell-driven. Currently, there are no effective therapeutic strategies to reduce kidney damage in these diseases despite growing concern for resulting long-term kidney dysfunction. The molecular mechanism(s) linking TLR signaling with suPAR expression and secretion is unknown. Our group discovered that deactivated CD11b was highly implicated in LN. CD11b is the alpha chain of the CD11b/CD18 integrin found on myeloid cells. Further investigation displayed that CD11b activation suppressed TLR signaling and reduced proinflammatory cytokine secretion in vivo. Furthermore, CD11b knock-in myeloid cells, from transgenic mice that express functionally active CD11b globally, had reduced suPAR secretion in vivo after stimulation with TLR ligands. Pharmacologic activation of CD11b by leukadherin-1 (LA1), developed in our lab, reduced suPAR secretion. Research so far hints that suPAR expression is downstream of TLR activation, thus, suppression of TLR signaling is a potential novel therapeutic approach against kidney injury. We hypothesize that CD11b activation, through CD11b agonist, LA1, will suppress TLR signaling, decreasing suPAR and proinflammatory cytokine levels, resulting in less kidney damage in patients. A multidisciplinary approach will be used to test this hypothesis through the flowing specific aims: 1.) Assess the inflammatory response and role of CD11b in LN and COVID-19; 2.) Define the molecular mechanism behind suPAR expression, and 3.) Determine the efficacy of LA1 as a potential therapeutic for kidney disease in these disease contexts. To achieve the scope of this project, extensive training in in vivo models, cell culture, molecular biology, and flow cytometry will occur. To expand my training, several resources are available to me at Rush University Graduate College, such as the Initiative to Maximize Student Development program and several research cores. Under the excellent mentorship of Dr. Vineet Gupta, and with the input of distinguished collaborators, Dr. Jochen Reiser, Dr. Sanja Sever, Dr. Paul Sanders, and Dr. Susan Quaggin, this project has the potential to provide excellent training, impact the field and open the doorway to development of novel therapeutics. To summarize, this project will investigate what drives LN and COVID-19 while evaluating therapeutics impacting the mechanisms behind kidney damage.