Neutrophils Play a Role in the Age-Related Decline of Hematopoietic Function
Hematopoietic stem cells and progenitor cells in the bone marrow produce the red blood cells and immune cells needed for the body to function. Changes in this hematopoietic system make up one the major factors in the age-related decline of the immune system into the incapacity of immunosenescence and chronic inflammatory state known as inflammaging. There is a decline in the diversity of cell populations tasked with producing immune cells, and the types of immune cell produced shifts to favor myeloid lineages of the innate immune system over lymphoid lineages of the adaptive immune system.
The age-related decline of the immune system is in part a feedback loop; dysfunction in immune cells produced in the bone marrow leads to inflammation and altered signaling in the bone marrow, leading to changes in production of immune cells, and consequent greater dysfunction in the immune system. Inflammatory signaling is the obvious suspect when considering how immune cells can disrupt stem cell function, but there are likely other mechanisms at work.
In this context, today's open access paper is interesting for the demonstration that the myeloid-derived neutrophil population plays a role in hematopoietic dysfunction with age. Unfortunately these cells are necessary to a robust immune defense, so one can't just take the approach used here, removing the entire neutrophil population. The next step must be to identify the specific mechanisms involved, and find ways to intervene at that level.
Myeloid cells promote interferon signaling-associated deterioration of the hematopoietic system
Hematopoietic stem cell (HSC) pools are positioned at the hematopoietic hierarchical apex and sustain multi-lineage hematopoiesis throughout the mammalian lifetime. They can do so by maintaining relative quiescence, self-renewal, and infrequent divisions during steady-state hematopoiesis. These critical processes are governed by ancillary cells in so-called stem cell niches, which include endothelial and mesenchymal cells in the mammalian hematopoietic system. Recent findings implicate resident innate and adaptive immune cells in the homeostatic regulation of stem cells. In particular, macrophages and regulatory T cells are established regulators of hematopoietic stem cells under homeostatic conditions.
The contribution of neutrophils, the most abundant innate immune cell in the human bone marrow, to homeostatic stem cell regulation, however, has remained largely elusive. This is mainly due to the lack of models fulfilling the experimental paradigm for defining HSC-regulating cells, which is (long-term) specific depletion of a candidate regulatory cell, followed by rigorous examination of HSC function. Existing models of neutropenia either induce transient, short-term reduction of neutrophil levels and/or employ genetic strategies that target HSCs themselves, precluding conclusions on the effect of neutropenia on long-term HSC biology.
Here, utilizing a mouse model of profound, sustained, and specific depletion of mature myeloid cells (neutrophils and eosinophils), we demonstrate that HSC integrity and function are conserved, implicating divergent responses of stem and progenitor cells to compensate for myeloid lineage shortages. Unexpectedly, the depletion of myeloid cells attenuated inflammatory signaling in stem cells and their niches via the reduction of natural killer (NK) cell numbers and activation status and abrogated the loss of HSC function in serial transplantation, identifying a neutrophil-NK cell axis as a critical determinant of the functional decline of the hematopoietic system.