Innate immune pathways and inflammation in hematopoietic aging, clonal hematopoiesis, and MDS

Abstract

With a growing aged population, there is an imminent need to develop new therapeutic strategies to ameliorate disorders of hematopoietic aging, including clonal hematopoiesis and myelodysplastic syndrome (MDS). Cell-intrinsic dysregulation of innate immune- and inflammatory-related pathways as well as systemic inflammation have been implicated in hematopoietic defects associated with aging, clonal hematopoiesis, and MDS. Here, we review and discuss the role of dysregulated innate immune and inflammatory signaling that contribute to the competitive advantage and clonal dominance of preleukemic and MDS-derived hematopoietic cells. We also propose how emerging concepts will further reveal critical biology and novel therapeutic opportunities.

Figure 1.

Proposed model of the step-wise progression of clonal hematopoiesis to MDS. (1) An initiating mutation, such as TET2, DNMT3A, or ASXL1, occurs within an HSC (green cell). (2) The mutant (“preleukemic”) HSPCs exhibit dysregulation of key SMOCs that control innate immune and inflammatory pathways. (3) Certain diseases and conditions, such as aging, autoimmune disorders, and chronic infections, can result in systemic inflammation characterized by increased alarmins and/or cytokines. (4) Preleukemic and MDS HSPCs (green cells), which have altered their response to the systemic effects of inflammation as a result of dysregulated SMOCs that control innate immune and inflammatory pathways, gain a competitive advantage over normal HSPCs (orange cells) in an environment associated with chronic inflammation (small red circles represent inflammatory mediators). In contrast, the inflammatory environment suppresses the normal HSPCs. (5) Over time, the mutant HSPCs acquire additional mutations that may lead to MDS (blue cells). (6) At the MDS stage, the mutant HSPCs gain further competitive advantage and exhibit impaired hematopoiesis. CH, clonal hematopoiesis.

Figure 2.

Cell-intrinsic dysregulation of SMOCs involved in innate immune, inflammasome, and inflammatory-related pathways in preleukemic and MDS HSPCs. TLRs recruit the adaptors TIRAP and MyD88, along with IRAK kinases and TRAF6, to form the myddosome complex. TLR3 and TLR4 can recruit the adaptors TRIF and TRAM, along with TBK and IKKe kinases and TRAF3, to form the trifosome complex. The inflammasome serves as a platform to activate Casp-1 through pyrin domain–containing receptors (i.e., NLRPs, AIM2, and Pyrin) and the adaptor proteins ASC or NLRC4. Activated Casp-1 cleaves signaling substrates, such as pro–IL-1β, leading to pyroptosis. Initiation of necroptosis is mediated by inflammatory ligands leading to RIPK1- and RIPK3-mediated activation of MLKL (“necroptosome”), which disrupts the plasma membrane integrity. The TGF-β superfamily signals through a dual receptor system of type I (ALK1, 2, and 5) and type II (TbRII) transmembrane serine/threonine kinases, leading to activation of the SMAD transcription factors. Although these SMOCs are characterized by distinct receptors and assembling adaptors and enzymes, they converge on critical downstream effectors (i.e., NF-κB, AP-1, IRFs, and SMADs) that affect preleukemic and MDS HSPC survival, self-renewal, proliferation, and migration. In addition, dysregulation of these pathways results in a differential sensitivity of HSPCs to systemic inflammation and the competitive advantage of preleukemia and MDS HSPCs. Genes/proteins in blue font are mutated and/or overexpressed in preleukemic and MDS HSPCs. Genes/proteins in red font are deleted, mutated, and/or down-regulated in preleukemic and MDS HSPCs. Casp-8, Caspase 8; dsDNA, double-stranded DNA; mut, mutant.