Heightened NLRP3 inflammasome activation is associated with aging and CMML diseases severity
Publisher DOI
Abstract
Aging causes chronic low-grade inflammation known as inflamm-aging. It is a risk factor for
chronic myelomonocytic leukemia (CMML), a hematological malignancy that is most
prevalent in older people. Recent studies suggest a critical role for the NLRP3 inflammasome
in inflamm-aging. However, the mechanisms involved in NLRP3 activation in aging and its
involvement in CMML progression are not fully understood. Here, we report that aging
increases interleukin-1β production upon NLRP3 activation in human CD14+ monocytes.
Interestingly, we found that Toll-like receptor (TLR) 1/2 agonist Pam3Cysk4 directly activates
NLRP3 inflammasome without the requirement of second activation signal in monocytes from
older but not from younger healthy donors. Further, we observed a dichotomous response to
NLRP3 inflammasome activation in monocytes from CMML patients. 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 cellular level, which may explain increased inflammation
and immune dysregulation in older individuals. Furthermore, NLRP3 inflammasome activation
was dysregulated in CMML and positively correlated with disease severity.
chronic myelomonocytic leukemia (CMML), a hematological malignancy that is most
prevalent in older people. Recent studies suggest a critical role for the NLRP3 inflammasome
in inflamm-aging. However, the mechanisms involved in NLRP3 activation in aging and its
involvement in CMML progression are not fully understood. Here, we report that aging
increases interleukin-1β production upon NLRP3 activation in human CD14+ monocytes.
Interestingly, we found that Toll-like receptor (TLR) 1/2 agonist Pam3Cysk4 directly activates
NLRP3 inflammasome without the requirement of second activation signal in monocytes from
older but not from younger healthy donors. Further, we observed a dichotomous response to
NLRP3 inflammasome activation in monocytes from CMML patients. 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 cellular level, which may explain increased inflammation
and immune dysregulation in older individuals. Furthermore, NLRP3 inflammasome activation
was dysregulated in CMML and positively correlated with disease severity.
Date Issued
2022-01-31
Publication Type
Working Paper
Subject(s)
Language(s)
en
Author(s)
Keller, Nino | |
Journal
biorxiv
Publisher
Cold Spring Harbor Laboratory
ISSN
2692-8205
Access(Rights)
open.access