Cell intrinsic dysregulation of innate immune signaling in MDS HSCs. TLRs and interleukin-1 receptor (IL-1R)/IL1RAP recruit MyD88 and IRAK4/2 (Myddosome complex) upon ligand binding (lipopolysaccharide [LPS], S100A alarmins, and IL-1). CD14 functions as a coreceptor of TLR4 in response to LPS. Toll-interleukin 1 receptor (TIR) domain containing adaptor protein (TIRAP) can also increase the efficiency of Myddosome assembly by binding MyD88. IRAK4, a serine/threonine kinase, activates IRAK2 and/or IRAK1 through IRAK4-dependent phosphorylation. IRAK1 activates the ubiquitin (Ub) ligase, TRAF6, which mediates signaling to NF-κB, MAPK, and RNA binding proteins (ie, hnRNPA1) through K63-linked Ub chains, leading to expression of proinflammatory cytokines and NLRP3 or splicing of the Rho guanosine triphosphatase–activating protein Arhgap. microRNA-146a (miR-146a) suppresses IRAK1 and TRAF6 protein expression. miR-145 suppresses TIRAP protein expression. TIFAB suppresses TRAF6 protein stability. Inflammosome activation results in caspase 1–dependent IL-1β processing and pyroptosis. Proteins and genes in green are downregulated and/or deleted in MDS. Proteins and genes in red are overexpressed and/or activated in MDS. Steps of the signaling pathway that have been pharmacologically inhibited are indicated. Adapted from Varney et al.¹¹²