Biology subjects

Jaggers, R. M.

Publications and source records attributed to Jaggers, R. M..

4 recordsLinked to original sources

bioRxiv2026

WISP1 drives a mechanically active immune modulatory and proliferative cardiac myofibroblast state

Pathological cardiac remodeling is driven by the proliferation and differentiation of resident fibroblasts into active myofibroblasts and results in excessive extracellular matrix (ECM) deposition and tissue stiffening. Expression of the matricellular protein WISP1 has previously been shown to be increased with cardiac fibrosis and promote myofibroblast activity, but the mechanisms by which this occurs remain unknown. Primary cardiac fibroblasts were isolated from adult mouse hearts and treated with recombinant WISP1 or TGF{beta}1 both alone and in combination to determine the functional role of the matricellular protein WISP1 in driving cardiac myofibroblast activity. WISP1 significantly increased alpha-smooth muscle actin and collagen type I expression, total collagen secretion, collagen gel contractility, and wound healing equally in fibroblasts from both male and female mice. However, WISP1 alone failed to induce expression of periostin, a hallmark myofibroblast marker, suggesting the resulting WISP1-dependent cell phenotype is unique and/or acting through non-canonical pathways. Indeed, inhibition of P38 MAPK completely ablated the WISP1-dependent increase in SMA and collagen expression, while having little to no impact on TGF{beta}1-dependent expression of myofibroblast marker genes. We next employed a multi-omics approach to define the functional impact of WISP1 on fibroblast cell-state within the transcriptome, cytosolic, and secreted ECM proteome. RNA-seq results show that WISP1 broadly promotes the expression of proliferative and immune modulatory genes at the transcriptomic level, while having very little impact on traditional myofibroblast and ECM modifying gene expression programs. At the proteome level, WISP1 was again a much weaker mediator of traditional myofibroblast and ECM proteins. However, in agreement with RNA-seq data, we observed a strong WISP1-dependent enrichment for proliferation-associated proteins in the cytosolic proteome and inflammation-associated proteins in the ECM proteome. Interestingly, WISP1 also showed a context-dependent response with TGF{beta}1, suggesting a more complex and yet to be elucidated signaling interaction between these independent mediators of myofibroblast activity. In conclusion, our data suggests that WISP1 promotes a unique proliferative and immune-modulatory myofibroblast phenotype. HighlightsO_LIWISP1 is sufficient to drive myofibroblast SMA and collagen expression and ECM deposition C_LIO_LIWISP1 promotes canonical myofibroblast contractility and wound healing activity C_LIO_LIWISP1 mediates myofibroblast activity via a non-canonical, P38 MAPK-dependent signaling pathway C_LIO_LIMulti-omics analysis of WISP1-dependent RNA and protein expression show that WISP promotes a proliferative and immune modulatory myofibroblast phenotype C_LI

cell biology↗

bioRxiv2025

β2 adrenergic receptors orchestrate neutrophil demargination and recruitment to the ischemic heart following myocardial infarction.

Neutrophils play a crucial role in instigating inflammation as well as its resolution post-myocardial infarction (MI). Although granulopoiesis in the bone marrow (BM) is the major source of cardiac neutrophils post-MI, infiltration of neutrophils to the heart occurs much quicker than peak granulopoiesis. These observations suggest that sources other than granulopoiesis may supply neutrophils to the heart during the early hours post-MI. Using a combination of flow cytometry, BM ablation of hematopoietic stem cells, confocal microscopy and multiple proteomics analysis, we found that the first wave of neutrophils recruited to the ischemic heart is exclusively sourced from vasculature and not from granulopoiesis in the BM/ spleen. The MI-evoked neutrophilia during the early hours bore all hallmarks of demargination induced by classical demarginating agents such as dexamethasone/ norepinephrine (NE). Various pharmacological and genetic strategies aimed at suppressing NE synthesis or disruption of {beta}-AR signaling reduced both neutrophil demargination as well as recruitment to the heart. Interestingly, however, despite a marked reduction in cardiac neutrophil burden only short-term inhibition of {beta}-ARs improved cardiac remodeling and function. Our findings support a pharmacological strategy to contain the initial onslaught of neutrophils on the ischemic heart using {beta}2-AR blockers to regulate the otherwise runaway inflammatory response.

immunology↗

bioRxiv2025

Cigarette smoke aggravates atherosclerosis by promoting the infiltration of inflammasome-primed neutrophils and disrupting macrophage function in lesions

BackgroundCigarette smoking (CS) is a major risk factor for cardiovascular disease (CVD) through chronic inflammation. While its pulmonary effects are well established, the mechanisms linking lung inflammation to vascular injury remain unclear. Because neutrophils are early responders to CS-induced inflammation, we hypothesized that they drive systemic myelopoiesis and vascular inflammation via alarmin release. MethodsWild-type (WT) mice were exposed to inhaled CS or orally administered cigarette smoke extract (CSE). Immune cell composition in lung, bronchoalveolar lavage fluid (BALF), blood, spleen, and bone marrow (BM) was assessed by flow cytometry. Hematopoietic stem and progenitor cell (HSPC) proliferation, reactive oxygen species (ROS) production, and S100A8/A9 release were quantified. Atherosclerosis progression was evaluated in Ldlr-/- mice fed a Western diet and treated with CSE. To define the role of neutrophil-derived S100A8/A9, bone marrow transplantation was performed using S100a9-/- or WT donors. ResultsCS exposure increased circulating monocytes and neutrophils through enhanced BM myelopoiesis and elevated ROS-dependent S100A8/A9 release. Oral CSE reproduced these effects, indicating direct activation of neutrophils independent of pulmonary inflammation or lipid changes. In Ldlr-/- mice, CSE accelerated atherosclerosis by promoting infiltration of inflammasome-primed neutrophils, increased IL-1{beta} release, and impaired macrophage efferocytosis. Hematopoietic S100a9 deletion normalized myelopoiesis and reduced vascular inflammation and plaque burden. ConclusionsIngested CS components directly activate neutrophils to release S100A8/A9, triggering myelopoiesis and vascular inflammation. These findings reveal that tobaccos cardiovascular toxicity extends beyond inhalation, implicating oral exposure as a driver of systemic inflammation and atherogenesis. Novelty and SignificanceO_ST_ABSWhat Is Known?C_ST_ABSO_LICigarette smoking (CS) is a major risk factor for atherosclerosis, driving systemic inflammation and innate immune activation. C_LIO_LINeutrophils and monocytes contribute to plaque progression, but the upstream mechanisms by which CS exacerbates their pathogenic roles remain incompletely understood. C_LIO_LIS100A8/A9 levels correlate with neutrophilia and cardiovascular risk in smokers, but their functional role in lesion biology is not fully defined. C_LI What New Information Does This Article Contribute?O_LIIdentifies S100A8/A9 as a key mediator linking CS exposure to enhanced medullary myelopoiesis, neutrophilia, and increased lesional infiltration of inflammasome-primed myeloid cells. C_LIO_LIDemonstrates that neutrophil-derived IL-1{beta} impairs macrophage efferocytosis by downregulating phagocytosis receptors, thereby promoting plaque vulnerability. C_LIO_LIReveals that CS drives atherosclerosis even in the absence of lipid perturbations or overt pulmonary injury, highlighting a novel oral exposure-vascular axis of disease propagation. C_LI

immunology↗

bioRxiv2021

Psychological stress disrupts intestinal epithelial cell function and mucosal integrity through microbe and host-directed processes

Psychological stress alters the gut microbiota and predisposes individuals to increased risk for enteric infections and chronic bowel conditions. Intestinal epithelial cells (IECs) are responsible for maintaining homeostatic interactions between the gut microbiota and its host. In this study, we hypothesized that disruption to colonic IECs is a key factor underlying stress-induced disturbances to intestinal homeostasis. Conventionally raised (CONV-R) and germ-free (GF) mice were exposed to a social disruption stressor (Str) to ascertain how stress modifies colonic IECs, the mucosal layer, and the gut microbiota. RNA sequencing of IECs isolated from CONV-R mice revealed a robust pro-inflammatory (Saa1, Il18), pro-oxidative (Duox2, Nos2), and antimicrobial (Reg3b/g) transcriptional profile as a result of Str. This response occurred concomitant to mucus layer thinning and signs of microbial translocation. In contrast to their CONV-R counterparts, IECs from GF mice or mice treated with broad spectrum antibiotics exhibited no detectable transcriptional changes in response to Str. Nevertheless, IECs from Str-exposed GF mice exhibited an altered response to ex vivo bacterial challenge (increased dual Oxidase-2 [Duox2] and nitric oxide synthase-2 (Nos2)), indicating that STR primes host IEC pro-oxidative responses. In CONV-R mice stress-induced increases in colonic Duox2 and Nos2 (ROS generating enzymes) strongly paralleled changes to microbiome composition and function, evidencing Str-mediated ROS production as a primary factor mediating gut-microbiota dysbiosis. In conclusion, a mouse model of social stress disrupts colonic epithelial and mucosal integrity, a response dependent on an intact microbiota and host stress signals. Together these preclinical findings may provide new insight into mechanisms of stress-associated bowel pathologies in humans.

immunology↗