Inflammatory signals regulate hematopoietic stem cells

Abstract

Hematopoietic stem cells (HSCs) are the progenitors of all blood and immune cells, yet their role in immunity is not well understood. Most studies have focused on the ability of committed lymphoid and myeloid precursors to replenish immune cells during infection. Recent studies, however, have indicated that HSCs also proliferate in response to systemic infection and replenish effector immune cells. Inflammatory signaling molecules including interferons, tumor necrosis factor-α and Toll-like receptors are essential to the HSC response. Observing the biology of HSCs through the lens of infection and inflammation has led to the discovery of an array of immune-mediators that serve crucial roles in HSC regulation and function.

Figure 1. Hematopoietic stem cells give rise to all the cell lineages of blood

Upon cell division, HSCs can achieve a variety of cell fates, including self-renewal or differentiation into cells with a more restricted differentiation potential. Long-term hematopoietic stem cells (LT-HSCs) are the most primitive, with a single cell able to entirely reconstitute the blood of an organism for an extensive period of time. Short-term HSCs (ST-HSCs) are similarly pluripotent, but their longevity is limited to a few months in the murine system . ST-HSCs give rise to multipotent progenitors (MPP), which are pluripotent cells that lack long-term reconstitution capability . The MPPs in turn differentiate into precursors that are committed to the lymphoid or myeloid lineages. These precursors, termed the common lymphoid progenitor (CLP) and common myeloid progenitor (CMP), represent the first major branching of the hematopoietic tree. CLPs give rise to B, T, and NK cells. CMPs give rise to the committed progenitor cells MEPs (megakaryocyte-erythroid progenitors) and GMPs (granulocyte-macrophage progenitors), which give rise to downstream differentiated progeny. As an example of the shifts that can occur in hematopoiesis with infection, those alterations that occur with chronic Mycobacterium avium infection are demonstrated . The cell populations that increase with infection are shown with a green background, and those that decrease are shown with a red background.

Figure 2. Inflammatory cytokine signaling pathways promote transcriptional changes to drive immune responses in hematopoietic cells

IFNα/β and IFNγ activate parallel signaling pathways. IFNα/β binding to the type I IFN receptor activates TYK2 and JAK1 to phosphorylate STAT1 and STAT2, which heterodimerize, associate with IRF9, and bind to ISREs to activate transcription. Signaling through the type II IFN receptor occurs in a parallel pathway. When IFNγ binds its receptor, associated JAK1 and JAK2 kinases phosphorylate STAT1, which homodimerizes and translocates to the nucleus for transcriptional activation at GAS sequences. The TNFα and TLR signaling pathways act similarly to promote transcriptional changes; these pathways exhibit extensive crosstalk. TNFα receptor binding causes TRADD to recruit RIP and TRAF2, which activate IKK to phosphorylate IκBa, thereby releasing NF-κB. TNFα receptor signaling also activates MEKK1, which causes JNK to stimulate AP-1 and ATF2. AP-1 binds TPA DNA-response elements (TRE), while ATF2 binds cAMP-responsive elements (CRE). Infectious particles activate TLRs to signal through MyD88, which recruits IRAK which binds TRAF6 and activates NF-κB and JNK pathways.

Figure 3. HSCs can be stimulated by cytokines via the systemic circulation

Upper panel: HSCs (blue) reside in the bone marrow niche amidst stromal cells (purple), separated from the bone matrix by osteoblasts (orange). Blood and circulating cytokines reach the bone marrow via small sinusoidal vessels. Lower panel: When systemic stresses, such as anemia or infection, stimulate production of cytokines, these factors travel in the blood to the HSC niche and can stimulate the HSC to proliferate, mobilize into the circulation or to differentiate into committed progenitors and immune effector cells.