The kinase activity of IRAK4 controls sterile autoinflammation and manifestations of Murine Lupus

Abstract

Interleukin-1 receptor-associated kinase (IRAK) 4 is a serine/threonine kinase involved in TLR/IL-1R responses. Upon TLR/IL-1R activation, autophosphorylation of IRAK4 induces proinflammatory gene transcription. In this study we hypothesize that the kinase activity of IRAK4 may be a druggable target in the treatment of sterile autoinflammation and Lupus. C57BL/6 female mice injected with the hydrocarbon oil Pristane, exhibited a significant Pristane-dependent induction of splenomegaly; whereas treatment with the IRAK4 kinase inhibitor reduced this inflammatory symptom. Conversely, no significant difference was observed in males. Using mass spectrometry, we found that the urine of Pristane-injected mice contained increased levels of putative markers for several inflammatory diseases, which were reduced by IRAK4 kinase inhibition. We showed that Pristane-injected mice had increased cell free DNA in serum, which was not impacted by kinase inhibitor treatment. However, chemokine release was significantly reduced in IRAK4 kinase inhibitor-treated mice. We further analyzed the kinase activity of IRAK4 in MRL-lpr mice, which were compared with MRL-lpr/IRAK4 kinase-inactive (KDKI) mice (where IRAK4 is expressed but its kinase activity is lost). Although MRL-lpr/IRAK4KDKI and MRL-lpr mice did not show differences in CD4+ and CD8+ cells activation, we found a significantly reduced splenomegaly in MRL-lpr/IRAK4KDKI mice compared to controls, also exhibiting a gender bias. Thus, IRAK4 kinase activity might represent a new therapeutic and druggable target in the recruitment of immune cells during sterile inflammatory diseases in humans, including Systemic Lupus Erythematous (SLE).