Identification of a forkhead box protein transcriptional network induced in human neutrophils in response to inflammatory stimuli, 2023, Ismailova+

[SNT Gatchaman]

Identification of a forkhead box protein transcriptional network induced in human neutrophils in response to inflammatory stimuli
Ismailova, Aiten; Salehi-Tabar, Reyhaneh; Dimitrov, Vassil; Memari, Babak; Barbier, Camille; White, John H.

Introduction: Neutrophils represent the largest proportion of circulating leukocytes and, in response to inflammatory stimuli, are rapidly recruited to sites of infection where they neutralize pathogens.

Methods and results: We have identified a novel neutrophil transcription network induced in response to inflammatory stimuli. We performed the first RNAseq analysis of human neutrophils exposed to lipopolysaccharide (LPS), followed by a meta-analysis of our dataset and previously published studies of LPS-challenged neutrophils. This revealed a robustly enhanced transcriptional network driven by forkhead box (FOX) transcription factors. The network is enriched in genes encoding proinflammatory cytokines and transcription factors, including MAFF and ATF3, which are implicated in responses to stress, survival and inflammation.

Expression of transcription factors FOXP1 and FOXP4 is induced in neutrophils exposed to inflammatory stimuli, and potential FOXP1/FOXP4 binding sites were identified in several genes in the network, all located in chromatin regions consistent with neutrophil enhancer function. Chromatin immunoprecipitation (ChIP) assays in neutrophils confirmed enhanced binding of FOXP4, but not FOXP1, to multiple sites in response to LPS. Binding to numerous motifs and transactivation of network genes were also observed when FOXP proteins were transiently expressed in HEK293 cells. In addition to LPS, the transcriptional network is induced by other inflammatory stimuli, indicating it represents a general neutrophil response to inflammation.

Discussion: Collectively, these findings reveal a role for the FOXP4 transcription network as a regulator of responses to inflammatory stimuli in neutrophils.

Link | PDF (Frontiers in Immunology)

 

[SNT Gatchaman]

Posting in relation to Genome-wide Association Study of Long COVID

We found that the most robustly enhanced transcriptional network, which is driven by forkhead box transcription factors, consists of genes that encode pro-inflammatory cytokines and transcription factors that are associated with inflammation and stress, such as MAFF and ATF3. Forkhead box transcription factors are characterized by the presence of a highly conserved forkhead DNA-binding domain. They possess overlapping binding specificities and are expressed in a cell specific manner.

We find that, among forkhead transcription factors, expression of FOXP1 and FOXP4 is enhanced in primary human neutrophils in response to LPS. This leads to enhanced binding of FOXP4, but not FOXP1, to multiple forkhead box motifs in network genes in neutrophils. Moreover, the network is induced in neutrophils by other inflammatory signals, such as a PKA agonist, GM-CSF and IFN-g, indicating that it is a component of neutrophil responses to inflammation.