Biology subjects

Campfield, B. T.

Publications and source records attributed to Campfield, B. T..

3 recordsLinked to original sources

bioRxiv2026

Follistatin-like 1 Promotes Neutrophil-mediated Host Defense against Klebsiella pneumoniae

Klebsiella pneumoniae is a leading cause of pneumonia and highly burdensome etiology of antibiotic-resistant infections constituting an urgent public health threat. Follistatin-like 1 (FSTL-1) is implicated in many processes including lung development and homeostasis, tissue remodeling, and inflammation though its role in antibacterial immunity remains poorly defined. We have observed that FSTL-1 is elevated in the lungs of both humans and mice during bacterial pneumonia. Using an inducible Fstl1 knockout mouse model, we demonstrate that FSTL-1 is required for pulmonary bacterial clearance and neutrophil recruitment during K. pneumoniae infection. Recombinant FSTL-1 rescues Fstl1-deficient susceptibility and enhances clearance of K. pneumoniae in wild-type mice. Mechanistically, FSTL-1-mediated protection was lost upon neutrophil depletion and in Cd14-deficient or Nr4a1 deficient mice, components of a lung-specific neutrophil transcriptional program. These findings identify FSTL-1 as a lung-derived factor that licenses neutrophil-mediated antibacterial defense via a novel FSTL-1/CD14/NR4A1-dependent signaling pathway critical for protection against bacterial pneumonia.

immunology↗

bioRxiv2026

A Novel Role for FSTL-1 in Hematopoietic Stem Cell Homeostasis and Post-injury Regeneration

Background: The ability to repopulate all lineages of blood cells from a single hematopoietic stem cell (HSC) requires a constant balancing between maintenance of quiescence/self-renewal and the need for differentiation and adoption of specific lineage phenotypes. A classical interpretation suggests that during homeostasis, long- and then short-term HSCs differentiate into multipotent progenitors (MPPs), which then lack self-renewal capacity but can still differentiate into all downstream lineages. While much is known about the intrinsic and extrinsic regulators that promote HSC homeostasis, less is known about factors which influence HSC behavior following significant bone marrow (BM) injury, such as sublethal irradiation (SLI). Methods: Conditional knock-out of follistatin-like 1 (FSTL-1) was achieved by breeding mice with floxed Fstl1 sites to mice expressing CreERT2 under control of the ROSA locus, followed by systemic tamoxifen administration. ELISA and RT-PCR quantitated protein and RNA level loss of FSTL-1, respectively. HSC populations were assessed by flow cytometry under multiple conditions. Sublethal irradiation induced BM injury and blocking polyclonal FSTL-1 antibodies were used to recapitulate results seen with genetic ablation. Finally, single cell RNA sequencing defined both cell-specific expression of Fstl1 within the BM compartment, but also identified transcripts and pathways upregulated in the absence of FSTL-1. Results: These studies delineate a novel role for FSTL-1 in regulating HSC biology. In addition to selective expression of Fstl1 within HSCs, genetic deletion of Fstl1 increases Lineage negative;Sca-1+c-Kit+ (LSK) cell number and alters HSC homeostasis. These findings are further amplified in the BM in the context of recovery from sublethal irradiation. Importantly, the post-irradiation increase in BM cellularity seen with Fstl1 deletion is replicated by treatment with anti-FSTL-1 polyclonal antibodies. Finally, single cell RNA sequencing reveals distinct Fstl1 expression in specific LSK subpopulations, including HSCs and proliferating cells, and identifies a novel relationship between decreased FSTL-1 levels and enrichment of canonical metabolic pathways including oxidative phosphorylation, fatty acid metabolism, and glycolysis. Conclusions: Taken together, these results highlight a novel role for FSTL-1 in promoting HSC homeostasis. They also unlock an innovative way to promote HSPC recovery following BM injury, knowledge predicted to be of significant therapeutic value.

developmental biology↗

bioRxiv2020

A Novel Role for the Nuclear Receptor, NR4A1, in Klebsiella pneumoniae Lung Infection

Klebsiella pneumoniae is a Gram-negative bacterial pathogen and common cause of pneumonia and bacteremia. Increasingly, K. pneumoniae has become a public health concern due to its rate of nosocomial infection and emerging, broad-spectrum antibiotic resistance. The nuclear receptor NR4A1 exhibits functionality in a multitude of organ systems and is implicated as having a role in the immune response to bacterial infection, though its role in K. pneumoniae infection is unknown. To determine if Nr4a1 functions in response to K. pneumoniae pulmonary disease, we infected wild-type and Nr4a1-/- mice with K. pneumoniae and assessed bacterial growth, immune cell recruitment and function, and cytokine production. We found that Nr4a1-/- mice had increased bacterial burden in the lungs and spleen, though no differences in cell recruitment. Pro-inflammatory cytokines, Il1{beta} and Il6, as well as chemokine, Cxcl2, were significantly decreased in the BAL fluid cells of Nr4a1-/- mice 5 hours post-infection. Additionally, Nr4a1-/- mice had reduced IL-1{beta} and myeloperoxidase protein production. We then examined the bactericidal function of macrophages and neutrophils from WT and Nr4a1-/- mice. We identified that Nr4a1-/- neutrophils had decreased bactericidal function compared to wild-type neutrophils, which was associated with reduced expression of Il1{beta}, Lcn2, Mpo, and Lyz2. These data suggest Nr4a1 plays a novel and essential role in neutrophil function during the host immune response to K. pneumoniae pulmonary infection.

immunology↗