Increased Inflammasome Activation Is Associated with Aging and Chronic Myelomonocytic Leukemia Disease Severity

Abstract

Aging causes chronic low-grade inflammation known as inflamm-aging. It is a risk factor for several chronic disorders, including chronic myelomonocytic leukemia (CMML), a hematological malignancy that is most prevalent in older people. Recent studies suggest a critical role for the NLRP3 (NOD-, LRR- and pyrin domain-containing protein 3) inflammasome in inflamm-aging. However, the mechanisms involved in NLRP3 activation in aging and its involvement in CMML progression are not fully understood. In this study, we report that aging increases IL-1β production upon NLRP3 activation in human CD14+ monocytes. Interestingly, we found that the TLR1/2 agonist Pam3CSK4 directly activates the NLRP3 inflammasome in monocytes from older but not from younger healthy donors. Furthermore, we observed a dichotomous response to NLRP3 inflammasome activation in monocytes from a small cohort of CMML patients, and some patients produced high levels of IL-1β and some patients produced low levels of IL-1β compared with older healthy donors. Intriguingly, CMML patients with heightened NLRP3 activation showed increased treatment dependency and disease severity. Collectively, our results suggest that aging causes increased sensitivity to NLRP3 inflammasome activation at a cellular level, which may explain increased inflammation and immune dysregulation in older individuals. Furthermore, NLRP3 inflammasome activation was dysregulated in a small cohort of CMML patients and was positively correlated with disease severity.

IL-1β–mediated inflammatory signaling drives ineffective erythropoiesis in early-stage myelodysplastic syndromes

“…Compared with those from yHDs, myelomonocytic cells from eHDs overexpressed genes involved in NF-κB signaling and inflammatory response pathways, including IL-1β (Supplemental Fig. 2c,d and Supplemental Table 6), which is consistent with the observation that aged myelomonocytes have increased inflammatory cytokine production 21 . CCUS myelomonocytic cells, which were highly metabolically active, exacerbated inflammatory signaling and overexpressed genes involved in IFN and complement responses (Fig.…”

High cell-free DNA is associated with disease progression, inflammasome activation and elevated levels of inflammasome-related cytokine IL-18 in patients with myelofibrosis

“…Whether elevated AIM2 might play a cooperating role in NLRP3 inflammasome activation in MF monocytes, as previously demonstrated for COVID19 monocytes (51), remains to be determined. In addition to poly(dA:dT), LPS plus nigericin also triggered higher IL-18 production in patients, indicating that other signals acting through NLRP3, such as S100A8/A9 (52), could contribute to NLRP3 inflammasome activation in vivo, as recently shown in monocytes from CMML patients (53). Considering that, besides inflammasomes, dsDNA stimulates several other inflammatory signals (20,21), elevated cfDNA could further contribute to MF inflammation by triggering additional inflammatory cascades.…”

Focus on the Function and Mechanism of Pyroptosis in Rheumatoid Arthritis

“…Recent research indicates that RA may be exacerbated by pyroptosis, a recently identified kind of controlled cell death. The NLRP3 inflammasome triggers caspase-1 during pyroptosis (53,54), which in turn triggers proinflammatory cytokines such IL-18 and interleukin (IL)-1β. Gasdermin D (GSDMD) can be cleaved by caspase-1 and other caspases, and the GSDMD-N-terminal (GSDMD-N) opens pores in the plasma membrane that allow substances like lactate dehydrogenase (LDH) to flow out (55,56).…”