Table 1. Experimental evidence for IRAK1 involvement in inflammatory and autoimmune diseases.
| Disease | Experimental System | Effector(s) | Effects |
|---|---|---|---|
| Sepsis [80] | CLP IRAK1-/y mouse | IRAK1 deficiency | Reduced mortality (35% vs. 85%); reduced plasma IL-6, IL-10 @6 hrs. |
| Sepsis [81] | LPS IRAK1-/- mouse | IRAK1 deficiency | Significantly reduced neutrophil infiltration, and tubular changes in liver and kidney. |
| Sepsis [85] | CLP mouse | MiRNA-146a | Reduced inflammatory cytokine levels, neutrophil infiltration, and cardiac dysfunction in miRNA-146a myocardial-transfected animals. |
| Sepsis [84] | MiRNA-146a -/- mouse | MiRNA-146a deficiency | Mir-146a -/- mice are hypersensitive to LPS challenge. |
| Sepsis [86] | PB neutrophils from sepsis pts | IRAK1 1595T haplotype | Increased neutrophil NF-κB; increased shock (OR 2.9, P = 0.047); prolonged mechanical ventilation (OR 2.7, P = 0.04); higher 60 d mortality (OR 2.7, P = 0.05). |
| Sepsis [87] | IRAK1 1595T haplotype | Increased need for prolonged mechanical ventilation (P = 0.02). | |
| Liver fibrosis [91] | CCL4 rat | miRNA-146a-5p | Levels of miRNA-146a-5p correlate with fibrosis progression. |
| Liver fibrosis [91] | LX-2 cells | miRNA-146a-5p | MiRNA-146a-5p transfection reduced proliferation, HSC activation. |
| Liver fibrosis [93] | STAM mouse | Pacritinib | Significantly reduced liver fibrotic area (P < 0.01) and CK-18 fragment levels (P < 0.05). |
| Myelofibrosis [32, 33] | Phase 3 clinical trials | Pacritinib | Increased platelet count in pts with <50,000/mL at BL; significantly increased Hgb in pts with <10g/dL and no transfusion at BL; significantly increased proportion of RBC transfusion independent pts in those who were transfusion dependent at BL. |
| GVHD [102] | BALB/c mouse allograft | Pacritinib | Significantly reduced mortality, but role of IRAK1 vs. JAK2 inhibition unknown. |
| GVHD [101] | AlloSCT pt whole blood RNA | MiRNA-146a | Levels of miRNA-146a were significantly associated with acute GVHD incidence at day 28 post-transplantation (OR 0.15, P = 0.016). |
| SLE [118] | Human DNA | IRAK1 rs1059702 SNP | An IRAK1 rs1059702 SNP is associated with SLE susceptibility (OR 1.43). |
| SLE [119] | Human DNA;B6.Sle1z.IRAK-/y andB6.Sle3z.IRAK-/y mice | IRAK1 SNPs | 5 IRAK1 SNPs were associated with increased SLE risk (OR>1.5). IRAK1 deficiency abrogated lupus-associated phenotypes in congenic mouse models. |
| SLE [25] | ABIN1 x IRAK1[D359A]-knock-in mice | Catalytically inactive IRAK1 | Crossing ABIN1 mice, which have a phenotype similar to human lupus, with mice having catalytically inactive IRAK1 prevented splenomegaly, autoimmunity, and liver and kidney inflammation. |
| SLE [48] | SLE pt PBMCs; B6.lpr mouse | IRAK1/4 inh 1; IRAK1 siRNA | IRAK1/4 inh significantly reduced renal injury in the B6.lpr model; IRAK1 is overexpressed in PBMCs from pts with SLE, and levels of NF-κB phosphorylation were reduced by IRAK1/4 inh I or IRAK1 siRNA. |
| Obesity [136] | Human adipose tissue | NA | IRAK1 gene expression higher in adipose tissue from obese vs. nonobese participants (P = 0.01) and correlated with TNFα mRNA in both pts with and without diabetes |
| Obesity [137] | Human adipocytes, WAT | MiRNA-146a | MiRNA-146a is elevated in obesity, blunts inflammatory response as measured by IL-8 and MCP-1, and reduces JNK and p38 activation. |
| T2D [39] | IRAK1-/- mouse | IRAK deficiency | IRAK1 KO mice had improved glucose tolerance, and insulin-stimulated glucose disposal rates and uptake in muscle (but not liver). Effects varied between high- and low-fat diets. |
| T2D [138] | T2D pt, control blood | MiRNA-146a | MiRNA-146a expression levels decreased in PBMCs (P = 0.004) and plasma (P = 0.008) of T2D pts (n = 30) relative to controls (n = 30); IRAK1 mRNA expression was increased in T2D pts (P = 0.028). |
| T2D [139] | STZ rats, DPN rats | T2D | MiRNA-146a expression and NCV decreased in DPN vs. STZ and normal rats (P < 0.01); TNFα, IL-1β, NF-κB correspondingly increase (P < 0.01); mIRNA-146a level negatively correlated with cytokines. |
| I/R [46] | Liver I/R mouse | MiRNA-146a | MiRNA-146a was decreased, IRAK1 increased in mouse Kupfer cells after I/R. MiR-146a overexpression decreased IRAK1, attenuated proinflammatory cytokines in H/R-induced macrophages. |
| I/R [140] | LAD ligated mouse | MiRNA-146a | MiRNA-146a transfection suppressed IRAK1 and TRAF6 expression, decreased infarct size by 50%, attenuated apoptosis, and protected against myocardial injury and cardiac dysfunction after I/R. |
| I/R [141] | Intestinal I/R IRAK1-/- mouse | MiRNA-146a | Intestinal IRAK1 levels increased after I/R in normal mice; tissue damage was reduced in KO mice. Induction of miR-146a protects against intestinal I/R injury. |
| I/R [142] | MCAO rat | IRAK1/4 inhibitor I | IRAK1/4 inhibition reduced mortality, neurological deficits, and ischemic infarct volume in MCAO rat, and was anti-apoptotic in a cellular model of hypoxia. |
ABIN1, A20-binding inhibitor of NF-κB; BL, baseline; CLP, cecal ligation and puncture; DPN, diabetic peripheral neuropathy; GVHD, graft-versus-host disease; Hgb, hemoglobin; H/R, hypoxia/reperfusion; hrs, hours; inh, inhibitor; I/R, ischemia/reperfusion injury; LAD, left anterior descending artery; LPS, lipopolysaccharide; MCAO, middle cerebral artery occlusion; NA, not applicable; NCV, nerve conduction velocity; OR, odds ratio; PBMC, peripheral blood mononuclear cells; pts, patients; RBC, red blood cell; STZ, streptozotocin-induced diabetic; WAT, white adipose tissue.