TY - JOUR
T1 - ZAKα/P38 kinase signaling pathway regulates hematopoiesis by activating the NLRP1 inflammasome
AU - Rodriguez-Ruiz, Lola
AU - Lozano-Gil, Juan M.
AU - Naranjo-Sánchez, Elena
AU - Martínez-Balsalobre, Elena
AU - Martínez-López, Alicia
AU - Lachaud, Christophe
AU - Blanquer, Miguel
AU - Phung, Toan K.
AU - García-Moreno, Diana
AU - Cayuela, María L.
AU - Tyrkalska, Sylwia D.
AU - Pérez-Oliva, Ana B.
AU - Mulero, Victoriano
N1 - Funding Information:
This work was supported by Fundacion Seneca, Agencia de Ciencia y Tecnologıa de la Region de Murcia (grants 20793/PI/18 and 21887/PI/22 to VM), MCIN/AEI/10.13039/501100011033 (research grant 2020-113660RB-I00) to VM, Juan de la Cierva-Incorporacion postdoctoral contract to SDT, and PhD fellowship to LR-R), ISCIII (Miguel Servet CP20/00028andCP21/00028 to ABP-O and DG-M, respectively), the Spanish Ministry of Universities (PhD fellowship to JML-G), Diamond-Blackfan Anemia Foundation, Inc. (DBAF), and Consejerıa de Salud de la CARM (ZEBER postdoctoral contract to AM-L).
Copyright:
© 2023 The Authors. Published under the terms of the CC BY 4.0 license.
PY - 2023/10/11
Y1 - 2023/10/11
N2 - Chronic inflammatory diseases are associated with hematopoietic lineage bias, including neutrophilia and anemia. We have recently identified that the canonical inflammasome mediates the cleavage of the master erythroid transcription factor GATA1 in hematopoietic stem and progenitor cells (HSPCs). We report here that genetic inhibition of Nlrp1 resulted in reduced number of neutrophils and increased erythrocyte counts in zebrafish larvae. We also found that the NLRP1 inflammasome in human cells was inhibited by LRRFIP1 and FLII, independently of DPP9, and both inhibitors regulated hematopoiesis. Mechanistically, erythroid differentiation resulted in ribosomal stress-induced activation of the ZAKα/P38 kinase axis which, in turn, phosphorylated and promoted the assembly of NLRP1 in both zebrafish and human. Finally, inhibition of Zaka with the FDA/EMA-approved drug Nilotinib alleviated neutrophilia in a zebrafish model of neutrophilic inflammation and promoted erythroid differentiation and GATA1 accumulation in K562 cells. In conclusion, our results reveal that the NLRP1 inflammasome regulates hematopoiesis and pave the way to develop novel therapeutic strategies for the treatment of hematopoietic alterations associated with chronic inflammatory and rare diseases.
AB - Chronic inflammatory diseases are associated with hematopoietic lineage bias, including neutrophilia and anemia. We have recently identified that the canonical inflammasome mediates the cleavage of the master erythroid transcription factor GATA1 in hematopoietic stem and progenitor cells (HSPCs). We report here that genetic inhibition of Nlrp1 resulted in reduced number of neutrophils and increased erythrocyte counts in zebrafish larvae. We also found that the NLRP1 inflammasome in human cells was inhibited by LRRFIP1 and FLII, independently of DPP9, and both inhibitors regulated hematopoiesis. Mechanistically, erythroid differentiation resulted in ribosomal stress-induced activation of the ZAKα/P38 kinase axis which, in turn, phosphorylated and promoted the assembly of NLRP1 in both zebrafish and human. Finally, inhibition of Zaka with the FDA/EMA-approved drug Nilotinib alleviated neutrophilia in a zebrafish model of neutrophilic inflammation and promoted erythroid differentiation and GATA1 accumulation in K562 cells. In conclusion, our results reveal that the NLRP1 inflammasome regulates hematopoiesis and pave the way to develop novel therapeutic strategies for the treatment of hematopoietic alterations associated with chronic inflammatory and rare diseases.
KW - anemia
KW - HSPCs
KW - inflammation
KW - neutrophilia
KW - zebrafish
UR - http://www.scopus.com/inward/record.url?scp=85170575152&partnerID=8YFLogxK
U2 - 10.15252/emmm.202318142
DO - 10.15252/emmm.202318142
M3 - Article
C2 - 37675820
SN - 1757-4676
VL - 15
JO - EMBO Molecular Medicine
JF - EMBO Molecular Medicine
IS - 10
M1 - e18142
ER -
