Cell-Targeted Inhibition of CaMK4 Suppresses Tertiary Lymphoid-like Structure Development in Lupus-Prone Mice.

Current treatment of lupus nephritis (LN) relies on broad immunosuppression and often fails to eradicate intrarenal immune niches that sustain inflammation. Tertiary lymphoid structures (TLS)-organized aggregates of immune cells forming in chronically inflamed non-lymphoid tissues-are increasingly recognized as drivers of local immune activation and tissue injury in LN. We previously showed that genetic CaMK4 deficiency suppresses autoimmunity and nephritis in lupus-prone mice. Here, we tested whether CaMK4 regulates renal TLS-like organization. Using kidneys from MRL/lpr mice that were CaMK4-deficient or treated with KN93-loaded nanoparticles targeted to CD4+ T cells or podocytes (anti-podocin), we compared findings with vehicle-treated controls. TLS-associated inflammation and maturation were quantified by mean fluorescence intensity of CD3, CD20, Ki67, and α-SMA. Across genetic and targeted-treatment arms, CaMK4 inhibition reduced all assessed markers, with uniform suppression of CD20 signal, highlighting a key role for B cells in TLS maintenance. Notably, podocyte-targeted KN93 most strongly suppressed TLS-like formation, implicating podocyte-driven pathways in interstitial inflammation and lymphoid neogenesis through previously underappreciated mechanisms. These data identify CaMK4 as a regulator of TLS-like architecture in LN and support the translational potential of cell-targeted CaMK4 inhibition to disrupt local immune recruitment while limiting systemic toxicity.