Defective Toll-Like Receptor Regulation May Predispose Individuals to MPNs

Patients who have myeloproliferative neoplasms (MPNs) have high levels of inflammatory cytokines. A recent study, published in Blood Advances, reports that monocytes from patients with MPNs have a defective negative regulation of Toll-like receptor (TLR) signaling that allows for the unrestrained production of tumor necrosis factor alpha (TNF) after TLR activation. Additionally, the authors write that TLR signaling not only contributes to chronic inflammation in patients with MPN, but also may predispose individuals to acquire MPNs.

TNF is produced by monocytes when TLRs are stimulated, and negative feedback TLR signaling is needed to avoid overproduction of TNF. The authors of the study sought to understand whether TLR signaling is exaggerated in patients with MPN.

The investigators obtained peripheral blood from patients with polycythemia vera (PV), essential thrombocythemia, or myelofibrosis, as well as from their family members and from healthy volunteers who served as controls. They then measured TNF production by cluster of differentiation (CD) 14-positive monocytes stimulated with TLR agonists, and the concentration of TNF was higher in the monocytes of patients with MPNs than in those of controls.

They also found that patients with MPN and controls had a similar fraction of CD14-positive and CD16-positive proinflammatory monocytes, so increased TNF production could not be explained by an increased fraction of monocytes actively producing TNF.

Failure to dampen TLR signaling, they say, may be responsible for persistent TNF production, and a defect in the TLR signaling negative feedback loop—namely, a blunted response to interleukin 10 (IL-10)—may be the cause. The degree of resistance to IL-10, they write, correlates with TNF persistence in patients with MPNs.

Notably, the investigators obtained monocytes from a patient with PV and from an unaffected twin sibling. Both the patient and the twin had prolonged production of TNF and IL-10, and the monocytes of the unaffected twin were less able to dampen TNF production. This suggests that the abnormality predates the development of MPN and may actually predispose individuals to acquire an MPN.

The authors add that, in addition to the chronic inflammation observed that results from dampened IL-10 signaling, it is likely that prolonged TLR signaling could extend to other immune cell populations, such as hematopoietic stem cells, and further studies should examine this possibility.

Reference

Lai HY, Brooks SA, Craver BM, et al. Defective negative regulation of toll-like receptor signaling leads to excessive TNF-a in myeloproliferative neoplasm. Blood Adv. 2019;3(2):122-131. doi: 10.1182/bloodadvances.2018026450.