Aug 2026· Science Advances· Vol 12· 0 citations· 98 references
Medicine
TL;DR
It is found that fibroblast recognition of interleukin-1 is essential for immune response and fibroblasts actively participate in innate immunity and highlight an IL-1R1–dependent keratinocyte-fibroblast-neutrophil axis of communication.
Abstract
Staphylococcus aureus can cause serious infections, yet it can also reside on the skin without causing disease. This apparent paradox implies a strong host defense system, which prevents S. aureus from invading the dermis. In this study, we investigate how the skin detects and responds to superficial S. aureus exposure. Using unbiased transcriptomic, biochemical, and phosphoproteomic analyses, followed by targeted validation in human and mouse models, we found that fibroblast recognition of interleukin-1 is essential for immune response. Deletion or blockade of the interleukin-1 receptor type 1 (IL-1R1) in fibroblasts in vitro abolished keratinocyte-driven changes in gene expression and reduced chemokine production. Furthermore, the skin of mice lacking fibroblast IL-1R1 had fewer neutrophils and higher bacterial load after topical S. aureus application. These findings show that fibroblasts actively participate in innate immunity and highlight an IL-1R1–dependent keratinocyte-fibroblast-neutrophil axis of communication. Understanding this pathway provides insights into mechanisms that initiate neutrophil recruitment to the skin and may help develop new approaches to therapy.
ABSTRACT Atopic dermatitis (AD) is a chronic pruritic skin condition characterized by lesions associated with colonization and infection by Staphylococcus aureus. There is growing evidence that S. aureus contributes to symptoms and persistence of AD through production of cytotoxins, superantigens, and proteases. When AD is treated with the interleukin-4 receptor blocking antibody, dupilumab, S. aureus colonization declines rapidly. Here, we examined the possible involvement of the host lysozyme-mediated innate immune response in helping to control S. aureus burden in AD patients. S. aureus is not killed by lysozyme, but the molecule inhibits S. aureus exotoxin and exoenzyme (exoprotein) production. Reduced S. aureus abundance during dupilumab treatment correlated positively with reduced lysozyme levels. S. aureus colonization and lysozyme levels were not altered in placebo-treated participants until they entered the open-label phase of the study (non-blinded phase) when all participants were treated with dupilumab. During that phase, the S. aureus and lysozyme levels declined. These findings suggest that AD patients may respond to cutaneous S. aureus colonization by upregulating lysozyme production. IMPORTANCE Staphylococcus aureus is increasingly viewed as an important contributor to atopic dermatitis (AD) persistence. The host responds to AD by producing cationic peptides, including lysozyme. Lysozyme cannot kill S. aureus, but the innate defense molecule downregulates exotoxin and exoenzyme production, limiting S. aureus-induced inflammation. Clinical improvement of AD likely requires balancing the inflammatory cascades induced by S. aureus versus host innate immunity. Staphylococcus aureus is increasingly viewed as an important contributor to atopic dermatitis (AD) persistence. The host responds to AD by producing cationic peptides, including lysozyme. Lysozyme cannot kill S. aureus, but the innate defense molecule downregulates exotoxin and exoenzyme production, limiting S. aureus-induced inflammation. Clinical improvement of AD likely requires balancing the inflammatory cascades induced by S. aureus versus host innate immunity.
P. Schlievert, S. Kilgore, E. Berdyshev et al.· Microbiology spectrum· 0 citations
Staphylococcus aureus is an opportunistic pathogen implicated in skin and soft-tissue infections and chronic inflammatory skin diseases, such as atopic dermatitis. These infections can range from mild to potentially life-threatening systemic illnesses progressing to bacteremia, endocarditis, and sepsis. Mast cells, traditionally recognized for their role in allergies, are highly abundant within the skin and are gaining recognition for their contribution to bacterial defense. Here, we discuss the role of mast cells in three models of S. aureus skin infection according to skin depth: epicutaneous sensitization, intradermal injections, and subcutaneous injections. During S. aureus skin infection, mast cells become activated and accumulate in infected skin, recognize bacterial toxins, and modulate the activity of other immune cells, including neutrophils and dendritic cells. We discuss areas of research that should be the target of future studies, such as neuroimmunology, infected excisional wounds, and risk of systemic illness. Our review aims to bring attention to the host-pathogen interaction between mast cells and S. aureus in the skin, both to encourage deeper investigation and inform the development of immunomodulatory-based therapeutics.
Hannah Dychtenberg, Carly Kadonoff, Bailey Lehnert et al.· Immunology and Cell Biology· 0 citations
It is shown that bone cells functionally express Mincle and indicated that this C-type lectin can mediate, at least in part, the inflammatory responses of OBs to SA challenge, which are attenuated following Mincle blockade.
Erin L. Mills, Quinton A. Krueger, Aiza Noyal et al.· Journal of Immunology· 0 citations
The findings suggest that S. aureus alters activation of the canonical type I IFN-mediated Jak-STAT pathway through suppression of STAT1 activation and altering chromatin remodeling and may alter the host response to this pathogen in a context-dependent manner and contribute to difficulty in clearing S. aureus infection.
Qiong Zhang, Ruoxi Yuan, Lionel B Ivashkiv· Journal of Immunology· 0 citations
Staphylococcus aureus remains a major cause of hospital‐ and community‐acquired infections, successfully evading host defense mechanisms and escaping proposed vaccination strategies. The effective response of professional phagocytes is crucial in limiting the spread, tissue invasion, and subsequent infection by S. aureus. However, direct stimulation of innate immunity with S. aureus antigens is too risky due to their strong proinflammatory properties. Therefore, this study aimed to test the hypothesis that plant extracts trigger the gentle release of staphylococcal bioactive components that can modulate innate immunity. This strategy was tested in vitro; however, it may have future applications by employing the resident microbiota and dietary supplements containing plant extracts. In this study, the THP‐1‐derived macrophages were exposed to the supernatants of planktonic and biofilm S. aureus cultures pretreated with Viburnum opulus L. bark and fruit extracts. Vancomycin (VAN) and chlorogenic acid (ChA), used at subinhibitory concentrations, were included for comparison regarding the release of S. aureus active components. The cells were also exposed to purified bacterial cell wall components. Various elements of the immune response were assessed, including surface expression of cluster of differentiation (CD11c, CD206) via flow cytometry, cytokine production (tumor necrosis factor‐alpha [TNF‐α] and interleukin 10 [IL‐10]) via ELISA, and S. aureus phagocytosis and intracellular killing using fluorescein isothiocyanate (FITC)‐labeled bacteria and Alamar Blue staining. It was demonstrated that both supernatants from planktonic and biofilm S. aureus cultures pre‐exposed to V. opulus extracts, as well as the bacterial cell wall components themselves, significantly increased TNF‐α and IL‐10 production by THP‐1‐derived macrophages and visibly reduced intracellular multiplication of engulfed S. aureus. The lack of changes in the surface CD marker expression may be a limitation of the model used (phorbol‐12‐myristate‐13‐acetate [PMA]‐differentiated THP‐1) rather than the phenomenon itself, that leads to a “ceiling effect”. To sum up, the study presents V. opulus extracts as the triggers to release bioactive components from S. aureus cells, able to target innate immunity against staphylococci, which may be used in the future.
Neurosurgical procedures such as craniotomies carry up to a 15% infection risk, predominantly due to Staphylococcus aureus (S. aureus) biofilms. These biofilms resist antibiotics and promote immune suppression, enabling chronic infection. Granulocytic myeloid-derived suppressor cells (G-MDSCs) emerge as key mediators of this immunosuppression, but the mechanisms driving their development, presumably from neutrophils, remain poorly defined.
We exposed bone marrow-derived neutrophils to S. aureus biofilm and analyzed phenotypic and functional changes via flow cytometry, RNA- sequencing, and T cell suppression assays. Genetic knockout models lacking Toll-like receptor 2 (TLR2) or MyD88 were used to delineate host signaling pathways. Additionally, we screened the S. aureus Nebraska Transposon Mutant Library (NTML) to identify bacterial factors responsible for neutrophil reprogramming.
Exposure to S. aureus biofilm transformed neutrophils into G-MDSC-like cells, exhibiting elevated CD11b, CD14, and PD-L1 expression, reduced bactericidal capacity, and suppression of T cell proliferation. TLR2-deficient neutrophils showed markedly reduced acquisition of these traits, while MyD88 deletion completely prevented the shift, implicating MyD88-dependent pathways. NTML screening identified specific bacterial TLR2 ligands as essential for driving this reprogramming.
Our findings reveal that S. aureus biofilms exploit TLR2-MyD88 signaling to reprogram neutrophils into immunosuppressive G-MDSC-like cells. This host-pathogen interaction underlies biofilm persistence and highlights both bacterial-derived TLR2 ligands and host TLR2 signaling as promising therapeutic targets to restore antimicrobial immunity in neurosurgical infections.
CHRI Mini grant
Microbial, Parasitic, and Fungal Immunology (MPF)
A. Ogunware, Gunjan Kak, Tammy Kielian et al.· Journal of Immunology· 0 citations
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