Biology subjects

Cameron, M. J.

Publications and source records attributed to Cameron, M. J..

4 recordsLinked to original sources

bioRxiv2026

Restoration of Keratinocyte Homeostasis Drives Resolution of Skin Inflammation

Chronic skin inflammation is sustained by reciprocal interactions between epidermal dysfunction and immune activation, yet whether epithelial state actively governs restoration of tissue homeostasis remains unclear. Using a murine model of inflammatory skin disease, we modulated epidermal lipid metabolism and examined its effects on tissue organization. Transcriptomic profiling revealed coordinated reversal of inflammatory, metabolic, and structural gene programs accompanied by normalization of epidermal architecture. Single-cell RNA sequencing showed that this remodeling was concentrated in differentiated keratinocytes, with suppression of IL-17 and neutrophil-associated responses and restoration of barrier and mitochondrial-lipid programs, while stromal and myeloid compartments displayed secondary adaptation. Cross-species analysis demonstrated that resolution-associated gene networks are inversely regulated in human psoriasis. Integrated proteomic and transcriptomic analyses further identified a conserved epithelial regulatory triad whose concordant regulation in psoriasis and atopic dermatitis, and whose in vivo silencing, establish mechanistic control of disease severity. Together, these findings indicate that inflammatory resolution reflects reorganization of epidermal transcriptional networks and position epithelial state as a determinant of inflammatory persistence.

cell biology↗

bioRxiv2022

Sex-specific niche signaling contributes to sexual dimorphism following stem cell transplantation

Hematopoietic stem cell (HSC) transplantation (HST) is a curative treatment for many hematopoietic cancers and bone marrow (BM) disorders but is currently limited by numerous complications including a lengthy recovery period, prolonged neutropenia resulting in severe infections and bleeding, and a high incidence of graft vs. host disease (GVHD). While clinical studies have demonstrated that sex mismatch, notably male recipients with female donor cells, results in increased risk of GVHD (likely due to male recipient minor histocompatibility antigens targeted by donor female T-cells 1), increased non-relapse mortality, and decreased overall survival, the mechanisms underlying sex-determinants on hematopoiesis and post-transplant recovery are not clear. In this manuscript we have identified: 1) unique expression of hematopoietic niche factors in the BM and spleens of male and female mice, 2) altered kinetics of hematopoietic reconstitution following transplantation when male vs. female BM is used as the donor cell source, 3) a sex-specific role for the recipient niche in promoting post HST recovery, and 4) a dose-dependent role for exogenous sex hormones in maintaining hematopoietic stem and progenitor cells (HSPCs). Taken together, these data demonstrate that sex-specific cellular and molecular signaling occurs during hematopoietic regeneration. Further identifying novel sex-dependent determinants of regeneration following transplantation will not only enhance understanding of steady state versus regeneration hematopoiesis but may also reveal unique (and potentially sex-specific) therapeutic targets to accelerate hematologic recovery. Key PointsO_LIMale and female mice display altered kinetics of regeneration following HST due to unique niche factors in hematopoietic compartments. C_LIO_LIExogenous steroid sex hormones uniquely regulate the pool of hematopoietic stem and progenitor cells and may impact transplantation outcomes. C_LI

immunology↗

bioRxiv2020

15-PGDH Inhibition Activates the Splenic Niche to Promote Hematopoietic Regeneration

The splenic microenvironment regulates hematopoietic stem and progenitor cell (HSPC) function, particularly during demand-adapted hematopoiesis, however practical strategies to enhance splenic support of transplanted HSPCs have proven elusive. We have previously demonstrated that inhibiting 15-hydroxyprostaglandin dehydrogenase (15-PGDH), using the small molecule (+)SW033291 (PGDHi), increases bone marrow (BM) prostaglandin E2 (PGE2) levels, expands HSPC numbers, and accelerates hematologic reconstitution following BM transplantation (BMT) in mice. Here we demonstrate that the splenic microenvironment, specifically 15-PGDH high-expressing macrophages (M{Phi}s), megakaryocytes (MKs), and mast cells (MCs), regulates steady-state hematopoiesis and potentiates recovery after BMT. Notably, PGDHi-induced neutrophil, platelet, and HSPC recovery were highly attenuated in splenectomized mice. PGDHi induced non-pathologic splenic extramedullary hematopoiesis at steady-state, and pre-transplant PGDHi enhanced the homing of transplanted cells to the spleen. 15-PGDH enzymatic activity localized specifically to M{Phi}s, MK lineage cells, and MCs, identifying these cell types as likely coordinating the impact of PGDHi on splenic HSPCs. These findings suggest that 15-PGDH expression marks novel HSC niche cell types that regulate hematopoietic regeneration. Therefore, PGDHi provides a well-tolerated strategy to therapeutically target multiple HSC niches and to promote hematopoietic regeneration and improve clinical outcomes of BMT.

cell biology↗

bioRxiv2019

Oral tenofovir disoproxil fumarate/emtricitabine for HIV pre-exposure prophylaxis increases expression of type I/III interferon-stimulated factors in the gastrointestinal tract but not in the blood

Tenofovir disoproxil fumarate (TDF) and emtricitabine (FTC) are used for HIV treatment and prevention. Previously, we found that topical rectal tenofovir gel caused immunological changes in the mucosa. Here we assessed the effect of oral TDF/FTC in three HIV pre-exposure prophylaxis trials, two with gastrointestinal and one with cervicovaginal biopsies. TDF/FTC induced type I/III interferon-related (IFN I/III) genes in the gastrointestinal tract, but not blood, with strong correlations between the two independent rectal biopsy groups (Spearman r=0.91) and between the rectum and duodenum (r=0.81). Gene set testing also indicated stimulation of type I/III pathways in the ectocervix, as well as of cellular proliferation in the duodenum. mRNA sequencing, digital droplet PCR, proteomics, and immunofluorescence staining confirmed IFN I/III pathway stimulation in the gastrointestinal tract. Thus, oral TDF/FTC stimulates an IFN-I/III signature throughout the gut, which could increase antiviral efficacy but also cause chronic immune activation in HIV prevention and treatment settings.

immunology↗