TY - JOUR
T1 - Increased Inflammasome Activation Is Associated with Aging and Chronic Myelomonocytic Leukemia Disease Severity
AU - Andina, Nicola
AU - de Meuron, Louise
AU - Schnegg-Kaufmann, Annatina Sarah
AU - Sarangdhar, Mayuresh Anant
AU - Ansermet, Camille
AU - Bombaci, Giuseppe
AU - Batta, Kiran
AU - Keller, Nino
AU - Porret, Naomi A
AU - Angelillo-Scherrer, Anne
AU - Bonadies, Nicolas
AU - Allam, Ramanjaneyulu
N1 - Copyright © 2023 by The American Association of Immunologists, Inc.
PY - 2023/3/1
Y1 - 2023/3/1
N2 - 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.
AB - 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.
KW - Humans
KW - Aged
KW - Inflammasomes
KW - NLR Family, Pyrin Domain-Containing 3 Protein
KW - Leukemia, Myelomonocytic, Chronic
KW - Aging
KW - Inflammation
KW - Patient Acuity
U2 - 10.4049/jimmunol.2200412
DO - 10.4049/jimmunol.2200412
M3 - Article
C2 - 36661356
SN - 0022-1767
VL - 210
SP - 580
EP - 589
JO - Journal of immunology (Baltimore, Md. : 1950)
JF - Journal of immunology (Baltimore, Md. : 1950)
IS - 5
ER -