Inflammatory signaling regulates hematopoietic stem and progenitor cell development and homeostasis

Abstract

Inflammation exerts multiple effects on the early hematopoietic compartment. Best studied is the role of proinflammatory cytokines in activating adult hematopoietic stem and progenitor cells to dynamically replenish myeloid lineage cells in a process known as emergency myelopoiesis. However, it is increasingly appreciated that the same proinflammatory signaling pathways are used in diverse hematopoietic scenarios. This review focuses on inflammatory signaling in the emergence of the definitive hematopoietic compartment during embryonic life, and tonic inflammatory signals derived from commensal microbiota in shaping the adult hematopoietic compartment in the absence of pathogenic insults. Insights into the unique and shared aspects of inflammatory signaling that regulate hematopoietic stem and progenitor cell function across the lifespan and health span of an individual will enable better diagnostic and therapeutic approaches to hematopoietic dysregulation and malignancies.

Figure 1.

Tonic inflammatory signaling in the establishment of definitive hematopoiesis. The development of HSCs involves three distinct steps. (1) Hemogenic endothelial cells respond to inflammatory signals secreted by primitive myeloid cells that converge on NF-κB to up-regulate Notch ligand. (2) Neighboring endothelial cells expressing Notch are stimulated to up-regulate a number of target genes required for HSC emergence; this signal is relayed in part through inflammatory pathways. (3) Mobilization of newly specified HSCs from the AGM into the circulation, migration to subsequent hematopoietic organs, and further functional maturation is regulated by cytokines. EMP, erythroid-myeloid progenitor; Mϕ, macrophage; Neu, neutrophil.

Figure 2.

Intestinal commensal microbes shape the hematopoietic compartment through systemic and niche effects. Commensal bacteria exert effects on type 3 innate lymphoid cells (ILC3s) within the intestinal lamina propria to produce IL17A, which stimulates circulating levels of G-CSF and acts distally on GMPs in the BM cavity. The intestinal microbiome also exerts distant effects on HSPCs by releasing bacterial products such as Nod1L that interact with the Nod1 receptor expressed on marrow MSCs and extracellular vesicles containing bacterial DNA that are taken up by Cx3cr1⁺ MNCs to stimulate the production of a whole range of cytokines that act locally within the BM microenvironment. The source of most of those circulating cytokines remains under investigation.