A conserved Foxp1-Pde4d axis regulates inflammatory responsiveness
- 1Institute for Neuroscience and Cardiovascular Research, University of Edinburgh
Abstract
Inflammatory responses are heterogeneous, even among cells exposed to a common insult, yet the regulatory mechanisms that distinguish these inflammatory states remain poorly understood. Here, we leveraged inflammatory state heterogeneity to identify a conserved Foxp1-Pde4d regulatory relationship and uncover a role for this axis in preserving inflammatory responsiveness. Genotoxic stress in adipocyte progenitors generated heterogeneous engagement of type-I interferon (IFN) and NF{kappa}B transcriptional programmes, and transcriptome-wide analysis independently identified Foxp1 and the cAMP phosphodiesterase Pde4d among genes associated with lower IFN- and higher NF{kappa}B-associated transcription. ChIP-seq revealed selective loss of Foxp1 occupancy at a Pde4d-associated regulatory element following genotoxic stress, while Foxp1 gain- and loss-of-function established Foxp1 as a positive regulator of Pde4d expression. Remarkably, coupling of Foxp1-Pde4d expression was broadly conserved across vertebrate tissues and damage models. In vivo, Foxp1 loss in zebrafish revealed a striking dissociation between inflammatory state and response capacity: basal NF{kappa}B activity was elevated, yet injury-induced NF{kappa}B activation was markedly blunted and macrophage recruitment impaired. Adenylyl cyclase inhibition restored macrophage recruitment in Foxp1-deficient zebrafish, functionally linking the Foxp1 phenotype to cAMP signalling and supporting a model in which Foxp1-Pde4d regulation preserves inflammatory responsiveness through control of cAMP. Together, these findings show how inflammatory-state heterogeneity can reveal conserved regulatory mechanisms linking basal cellular state to subsequent response capacity.
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BibTeX
@misc{elemans2026conserved,
title = {{A conserved Foxp1-Pde4d axis regulates inflammatory responsiveness}},
author = {L. M. Elemans and P. Tandon and G. Rodger and L. Stirling and S. Hendry and M. N. Akhtar and X. Chen and T. Mitic and Y. Feng and R. K. Semple and J. E. Minchin},
howpublished = {bioRxiv},
year = {2026},
month = oct,
doi = {10.64898/2026.10.27.762160},
url = {https://www.biorxiv.org/content/10.64898/2026.10.27.762160v1},
note = {CC BY},
}
RIS
TY - UNPB
TI - A conserved Foxp1-Pde4d axis regulates inflammatory responsiveness
AU - L. M. Elemans
AU - P. Tandon
AU - G. Rodger
AU - L. Stirling
AU - S. Hendry
AU - M. N. Akhtar
AU - X. Chen
AU - T. Mitic
AU - Y. Feng
AU - R. K. Semple
AU - J. E. Minchin
PY - 2026
DA - 2026/10/27
PB - bioRxiv
DO - 10.64898/2026.10.27.762160
UR - https://www.biorxiv.org/content/10.64898/2026.10.27.762160v1
AB - Inflammatory responses are heterogeneous, even among cells exposed to a common insult, yet the regulatory mechanisms that distinguish these inflammatory states remain poorly understood. Here, we leveraged inflammatory state heterogeneity to identify a conserved Foxp1-Pde4d regulatory relationship and uncover a role for this axis in preserving inflammatory responsiveness. Genotoxic stress in adipocyte progenitors generated heterogeneous engagement of type-I interferon (IFN) and NF{kappa}B transcriptional programmes, and transcriptome-wide analysis independently identified Foxp1 and the cAMP phosphodiesterase Pde4d among genes associated with lower IFN- and higher NF{kappa}B-associated transcription. ChIP-seq revealed selective loss of Foxp1 occupancy at a Pde4d-associated regulatory element following genotoxic stress, while Foxp1 gain- and loss-of-function established Foxp1 as a positive regulator of Pde4d expression. Remarkably, coupling of Foxp1-Pde4d expression was broadly conserved across vertebrate tissues and damage models. In vivo, Foxp1 loss in zebrafish revealed a striking dissociation between inflammatory state and response capacity: basal NF{kappa}B activity was elevated, yet injury-induced NF{kappa}B activation was markedly blunted and macrophage recruitment impaired. Adenylyl cyclase inhibition restored macrophage recruitment in Foxp1-deficient zebrafish, functionally linking the Foxp1 phenotype to cAMP signalling and supporting a model in which Foxp1-Pde4d regulation preserves inflammatory responsiveness through control of cAMP. Together, these findings show how inflammatory-state heterogeneity can reveal conserved regulatory mechanisms linking basal cellular state to subsequent response capacity.
ER -