Deficiency in IRAK4 activity attenuates manifestations of murine Lupus

Abstract

Interleukin-1 receptor-associated kinase (IRAK) 4 mediates host defense against infections. As an active kinase, IRAK4 elicits full spectra of myeloid differentiation primary response protein (MyD) 88-dependent responses, while kinase-inactive IRAK4 induces a subset of cytokines and negative regulators whose expression is not regulated by mRNA stability. IRAK4 kinase activity is critical for resistance against Streptococcus pneumonia, but its involvement in autoimmunity is incompletely understood. In this study, we determined the role of IRAK4 kinase activity in murine lupus. Lupus development in BXSB mice expressing the Y chromosome autoimmunity accelerator (Yaa) increased basal and Toll-like receptor (TLR) 4/7-induced phosphorylation of mitogen-activated protein kinases, p65 nuclear factor-κB (NF-κB), enhanced tumor necrosis factor (TNF)-α and C-C motif chemokine ligand (CCL) 5 gene expression in splenic macrophages, but decreased levels of Toll-interacting protein and IRAK-M, without affecting IRAK4 or IRAK1 expression. Mice harboring kinase-inactive IRAK4 on the lupus-prone Yaa background manifested blunted TLR signaling in macrophages and reduced glomerulonephritis, splenomegaly, serum anti-nuclear antibodies, numbers of splenic macrophages, total and TNF-α+ dendritic cells, activated T- and B-lymphocytes, and lower TNF-α expression in macrophages compared to lupus-prone mice with functional IRAK4. Thus, IRAK4 kinase activity contributes to murine lupus and could represent a new therapeutic target.

TLR7 Protein Expression in Mild and Severe Lupus-Prone Models Is Regulated in a Leukocyte, Genetic, and IRAK4 Dependent Manner

“…Aside from Myddosome signaling, IRAK4 also plays a structural, kinase-independent role, which can mediate TAK1-independent NF-κB activation (37, 41). Our data and the work of others has effectively eliminated this as a major factor in the development of autoimmune traits (42, 45). Additionally, in this study, we comprehensively analyzed TLR7 protein expression across leukocyte subsets infiltrating the kidney, and in the spleen.…”

“…Sle1 / Sle1 Tg7 mice was the retention of the same non-autoimmune background (B6), eliminating influences of other loci. In these studies, we were able to confirm that the elimination of proteinuria and splenomegaly seen in BXSB Yaa .IRAK4 KD/KD mice was not due to the dilution of susceptibility loci present in the BXSB background by the introduction of the B6 non-autoimmune genome (45). However, in contrast to the data from Murphy et al our heterozygous Sle1 Tg7IRAK4 WT/KD mice developed severe disease in a similar manner to Sle1 Tg7IRAK4 KD /IRAK4 KD homozygotes (data not shown).…”

“…Additionally, the role of TLR signaling and regulatory molecules was assessed in the BXSB lupus-prone model (45). The aggressive lupus-like phenotypes in the male are driven by a 2-fold increase in TLR7 expression due to the presence of the yaa locus (21, 23, 24).…”

“…Elimination of IRAK4 kinase activity in BXSB. IRAK4 ki/ki F2 mice resulted in a reduction in splenomegaly and number of splenic F4/80+ macrophages, neutrophils, total B cells, plasmablasts, and total CD11c + cells (45). Supporting these findings, in vivo administration of a selective inhibitor of IRAK4, BMS-986126, prevented the development of GN, plasma anti-dsDNA autoantibodies and reduced IFNa + pDCs in both NZB/W and MRL lpr mice, and splenic IL-6 + CD11b + myeloid cells in latter (46).…”

Jieduquyuziyin Prescription Suppresses Inflammatory Activity of MRL/lpr Mice and Their Bone Marrow-Derived Macrophages via Inhibiting Expression of IRAK1-NF-κB Signaling Pathway

“…However, symptoms in the JP group were alleviated ( Figure 5 ). Studies have unveiled the promoted levels of TNF-α and C-C Motif Chemokine Ligand 5 (CCL5) mRNA provoked by TLR4 and TLR7 in spleen macrophages of lupus-susceptible mice ( Murphy et al., 2017 ). The spleen of mice in the model group also showed pathological conditions, such as splenomegaly ( Zhang et al., 2019 ).…”