The role of circulating monocytes and JAK inhibition in the infectious-driven inflammatory response of myelofibrosis

Abstract

Myelofibrosis (MF) is characterized by chronic inflammation and hyper-activation of the JAK-STAT pathway. Infections are one of the main causes of morbidity/mortality. Therapy with Ruxolitinib (RUX), a JAK1/2 inhibitor, may further increase the infectious risk. Monocytes are critical players in inflammation/immunity through cytokine production and release of bioactive extracellular vesicles. However, the functional behavior of MF monocytes, particularly during RUX therapy, is still unclear. In this study, we found that monocytes from JAK2V617F-mutated MF patients show an altered expression of chemokine (CCR2, CXCR3, CCR5) and cytokine (TNF-α-R, IL10-R, IL1β-R, IL6-R) receptors. Furthermore, their ability to produce and secrete free and extracellular vesicles-linked cytokines (IL1β, TNF-α, IL6, IL10) under lipopolysaccharides (LPS) stimulation is severely impaired. Interestingly, monocytes from RUX-treated patients show normal level of chemokine, IL10, IL1β, and IL6 receptors together with a restored ability to produce intracellular and to secrete extracellular vesicles-linked cytokines after LPS stimulation. Conversely, RUX therapy does not normalize TNF-R1/2 receptors expression and the LPS-driven secretion of free pro/antiinflammatory cytokines. Accordingly, upon LPS stimulation, in vitro RUX treatment of monocytes from MF patients increases their secretion of extracellular vesicles-linked cytokines but inhibits the secretion of free pro/anti-inflammatory cytokines. In conclusion, we demonstrated that in MF the infection-driven response of circulating monocytes is defective. Importantly, RUX promotes their infection-driven cytokine production suggesting that infections following RUX therapy may not be due to monocyte failure. These findings contribute to better interpreting the immune vulnerability of MF and to envisaging strategies to improve the infection-driven immune response.

Liquid Biopsy and Potential Liquid Biopsy-Based Biomarkers in Philadelphia-Negative Classical Myeloproliferative Neoplasms: A Systematic Review

“…After we excluded the irrelevant manuscripts based on the screening of their titles and abstracts ( n = 81), we examined the full texts of 33 manuscripts. Finally, after we applied the exclusion and inclusion criteria, 27 original articles were included in this review [ 15 , 16 , 17 , 18 , 19 , 20 , 21 , 22 , 23 , 24 , 25 , 26 , 27 , 28 , 29 , 30 , 31 , 32 , 33 , 34 , 35 , 36 , 37 , 38 , 39 , 40 , 41 ].…”

“…The analyzed studies investigated the levels of cell-free DNA ( n = 1), extracellular vesicles ( n = 7), microparticles ( n = 14) or circulating endothelial cells ( n = 5) levels in MPNs. Flow cytometry was by far the most employed method of detection ( n = 23) [ 15 , 16 , 17 , 18 , 19 , 20 , 21 , 22 , 23 , 24 , 25 , 26 , 27 , 28 , 29 , 30 , 31 , 32 , 33 , 34 , 35 , 36 , 37 , 38 , 39 , 40 , 41 ].…”

Genetics and Pathogenetic Role of Inflammasomes in Philadelphia Negative Chronic Myeloproliferative Neoplasms: A Narrative Review

“…The evidence of immunological dysregulation in PMF derives also from the murine Gata1 low mouse model, which shows a high level of TGF-β1 and collagen in megakaryocytes and abnormal signature in TGF-β1 signaling gene expression in spleen and marrow [ 34 , 35 , 36 ]. The dysregulation of immune system in MPNs stems, in part, from the defective differentiation of monocytes into dendritic cells [ 37 ] and from their inability to produce and release cytokines, such as IL-1β, TNF-α, IL-6 and IL-10, in response to infectious stimulus and to migrate into damaged tissues [ 38 , 39 ].…”

The “Vesicular Intelligence” Strategy of Blood Cancers

“…Also, we recently demonstrated that circulating monocytes from JAK2 V617F-mutated MF patients are dysregulated and show a reduced in vitro ability to produce/secrete inflammatory cytokines in response to an infectious stimulus. Surprisingly, the JAK1/2 inhibitor Ruxolitinib promotes the EV-based inflammatory cytokine signaling [ 116 ].…”