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Thioredoxin domain-containing protein 12 (TXNDC12) is a member of the thioredoxin-like superfamily that contributes to various thiol-dependent metabolic activities in all living organisms. In this research, the TXNDC12 gene from yellowtail clownfish (Amphiprion clarkii) was structurally characterized using in silico tools, assessed for immunological expression, and evaluated for biological activity using recombinant protein and cellular overexpression. The deduced coding sequence of AcTXNDC12 comprised a 522-bp nucleotide, encoding 173 amino acids with a predicted molecular mass of 19.198 kDa. The AcTXNDC12 protein consists of a 66 WCGAC 70 active motif and a 170 GDEL 173 signature. The highest tissue-specific expression of AcTXNDC12 was observed in the brain tissue, with significant modulation observed in the blood and gill tissues following stimulation of polyinosinic: polycytidylic acid, lipopolysaccharides (LPS), and Vibrio harveyi. In functional assays, recombinant AcTXNDC12 protein (rAcTXNDC12) showed insulin disulfide reduction activity, 2,2'-azino-di-(3-ethylbenzthiazoline sulfonic acid) decolorization antioxidant capacity, and ferric (Fe 3+ ) reducing antioxidant potential. Additionally, a significant reduction in nitric oxide production was observed in AcTXNDC12-overexpressed RAW 264.7 cells upon LPS stimulation. Furthermore, genes associated with the regulation of oxidative stress, including nuclear factor erythroid 2-related factor 2 (Nrf2), catalase (Cat), peroxiredoxin 1 (Prx1), and ribonucleotide reductase catalytic subunit M1 (Rrm1) were significantly upregulated in fathead minnow cells overexpressing AcTXNDC12 in response to H 2 O 2 treatment. The scratch wound healing assay demonstrated tissue regeneration and cell proliferation ability upon AcTXNDC12 overexpression. Altogether, the current study elucidated the antioxidant activity, immunological importance, and wound-healing effect of the AcTXNDC12 gene in yellowtail clownfish, providing valuable insights for advancing the aquaculture of A. clarkii fish., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

The skin microbiome can both trigger beneficial immune stimulation and pose a potential infection threat. Previous studies have shown that colonization of mouse skin with the model human skin commensal Staphylococcus epidermidis is protective against subsequent excisional wound or pathogen challenge. However, less is known about concurrent skin damage and exposure to commensal microbes, despite growing interest in interventional probiotic therapy. In this study, we address this open question by applying commensal skin bacteria at a high dose to abraded skin. Although depletion of the skin microbiome through antibiotics delayed repair from damage, probiotic-like application of commensals-including the mouse commensal Staphylococcus xylosus, 3 distinct isolates of S. epidermidis, and all other tested human skin commensals-also significantly delayed barrier repair. Increased inflammation was observed within 4 hours of S. epidermidis exposure and persisted through day 4, at which point the skin displayed a chronic wound-like inflammatory state with increased neutrophil infiltration, increased fibroblast activity, and decreased monocyte differentiation. Transcriptomic analysis suggested that the prolonged upregulation of early canonical proliferative pathways inhibited the progression of barrier repair. These results highlight the nuanced role of members of the skin microbiome in modulating barrier integrity and indicate the need for caution in their development as probiotics., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Diabetic foot ulcers (DFU), affecting a quarter of diabetic patients and leading to high rates of amputation and mortality, pose significant health and economic burdens. Wound healing in DFU is often compromised by chronic inflammation, underscoring the critical role of immune cells. However, the systematic investigation of immune-related genes (IRGs) in DFU pathogenesis remains elusive. To address this gap, our study aims to explore the association between IRGs and DFU., Methods: To explore biological changes in immune related gene expression in DFU, RNA-seq was performed on wound biopsies derived from 10 DFU patients and 11 healthy controls. Differentially expressed genes (DEGs) between DFU and normal samples were obtained by DEseq2. By intersecting the IRG list from the ImmPort database, the immune-related differentially expressed genes were identified. Function enrichment analysis and protein-protein interaction (PPI) analysis were applied by clusterProfiler and STRING database, and the hub genes of the PPI network were calculated by the cytoHubba plug-ins in Cytoscape. CIBERSORT algorithms was applied to analyze immune infiltration in DFU. And the correlation between immune cells infiltration and hub genes was explored by correlation analysis. Finally, to validate our findings, the transcriptional change of hub genes in DFU was confirmed using external scRNA-seq dataset and RT-qPCR., Results: RNA-seq analysis detected 8,800 DEGs in DFUs, with 2,351 upregulated and 6,449 downregulated.526 differential IRGs were obtained from intersection of DEGs and IRGs. 526 differential IRGs were obtained from intersection of DEGs and IRGs. Enrichment function analysis of DEGs showed that they played a significant role in immune response. The PPI network was constructed, and the most significant module containing 4 hub genes was identified. CIBERSORT analysis showing that there was a significant difference between DFU and normal controls in the infiltration of immune cells. Compared with normal tissue, DFU tissue contained a higher proportion of resting NK cell, M0 macrophages, and activated mast cell, while resting dendritic cell, activated mast cell, and activated NK cell contributed to a relatively lower portion. Additionally, the analysis for M1/M2 polarization of macrophage cells shown that DFU tissue contained a higher M1/M2 ratio than normal group. Finally, the expression levels of 4 hub genes were confirmed by external scRNA-seq dataset and RT-qPCR., Conclusions: The immune related hub genes and the difference in immune infiltration between DFU tissue and normal controls might provide new insight for understanding DFU healing., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Regulatory T cells (Tregs) are crucial immune cells for tissue repair and regeneration. However, their potential as a cell-based regenerative therapy is not yet fully understood. Here, we show that local delivery of exogenous Tregs into injured mouse bone, muscle, and skin greatly enhances tissue healing. Mechanistically, exogenous Tregs rapidly adopt an injury-specific phenotype in response to the damaged tissue microenvironment, upregulating genes involved in immunomodulation and tissue healing. We demonstrate that exogenous Tregs exert their regenerative effect by directly and indirectly modulating monocytes/macrophages (Mo/MΦ) in injured tissues, promoting their switch to an anti-inflammatory and pro-healing state via factors such as interleukin (IL)-10. Validating the key role of IL-10 in exogenous Treg-mediated repair and regeneration, the pro-healing capacity of these cells is lost when Il10 is knocked out. Additionally, exogenous Tregs reduce neutrophil and cytotoxic T cell accumulation and IFN-γ production in damaged tissues, further dampening the pro-inflammatory Mo/MΦ phenotype. Highlighting the potential of this approach, we demonstrate that allogeneic and human Tregs also promote tissue healing. Together, this study establishes exogenous Tregs as a possible universal cell-based therapy for regenerative medicine and provides key mechanistic insights that could be harnessed to develop immune cell-based therapies to enhance tissue healing., (© 2024. The Author(s).)

Skin-resident regulatory T cells (Tregs) play an irreplaceable role in orchestrating cutaneous immune homeostasis and repair, including the promotion of hair regeneration via the Notch signaling ligand Jagged-1 (Jag1). While skin Tregs are indispensable for facilitating tissue repair post-wounding, it remains unknown if Jag1-expressing skin Tregs impact wound healing. Using a tamoxifen inducible Foxp3 creERT2 Jag1 fl/fl model, we show that loss of functional Jag1 in Tregs significantly delays the rate of full-thickness wound closure. Unlike in hair regeneration, skin Tregs do not utilize Jag1 to impact epithelial stem cells during wound healing. Instead, mice with Treg-specific Jag1 ablation exhibit a significant reduction in Ly6G + neutrophil accumulation at the wound site. However, during both homeostasis and wound healing, the loss of Jag1 in Tregs does not impact the overall abundance or activation profile of immune cell targets in the skin, such as CD4+ and CD8+ T cells, or pro-inflammatory macrophages. This collectively suggests that skin Tregs may utilize Jag1-Notch signalling to co-ordinate innate cell recruitment under conditions of injury but not homeostasis. Overall, our study demonstrates the importance of Jag1 expression in Tregs to facilitate adequate wound repair in the skin., (© 2024. The Author(s).)

Acute injuries trigger an intense activation of the body's defense mechanisms aiming to limit damage and initiate healing. Among the crucial components of the intravascular immune system, the complement system plays a significant role in traumatic injuries, albeit often negatively. It has been suggested that excessive activation of the complement system, transitioning from a localized and timed response to a systemic one, can lead to a loss of its host-protective characteristics. Complement activation products have been associated with the severity of injuries, which sometimes serve as predictors for the onset of organ dysfunctions. Animal studies utilizing complement-targeting agents have provided the basis for considering complement in the management of traumatic injuries in humans. However, numerous studies suggest that the spatial and temporal aspects of complement inhibition are crucial for its efficacy. Understanding the underlying mechanism of the injury is essential to determine where, when, and whether complement inhibition is warranted. Despite the detrimental effects of uncontrolled complement activation, its regulated activation may contribute to essential aspects of healing, such as waste removal and regeneration. This review focuses on the beneficial roles of complement activation in trauma, which are often overlooked or given less consideration but are of immense importance., (© 2024 The Author(s). European Journal of Immunology published by Wiley‐VCH GmbH.)

Introduction: Adipose-derived stem cells (ASCs) are multipotent stem cells capable of differentiating into many cell lineages. They play an important role in wound healing by secreting cytokines. Prior studies have demonstrated the presence of proinflammatory cytokines in burn wounds. However, no studies have been performed evaluating the cytokines released by burn wounds with infections. We hypothesized that there is an alteration in the paracrine factors secreted by ASCs in burn wounds with concomitant infections., Methods: Adipose tissue was collected from patients with burn injuries at their index operation. ASCs were extracted and grown under standard tissue culture techniques. The supernatant was extracted. Cytokine analyses were performed with multiplex assays. Infection was determined using a burn sepsis protocol. The cytokine profiles of the two groups were compared using a Mann-Whitney U test., Results: Sixteen patients were enrolled in the study, 50% with bacterial infection (n = 8). There was no significant difference in the baseline demographics of the two groups (P > 0.05). There were significantly lower concentrations of interleukin 13 and interferon gamma (P < 0.05) in burn patients with concomitant infections., Conclusions: ASCs are critical to burn wound healing. This study demonstrated diminished production of interleukin 13, an immunoregulatory cytokine involved in the antiinflammatory pathway by downregulating macrophage activity. This study also demonstrated significantly lower levels of interferon gamma in patient with burns and concomitant infection. This cytokine is crucial for antimicrobial defenses., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Significance: The incidence of diabetes continues to rise throughout the world in an alarming rate. Diabetic patients often develop diabetic foot ulcers (DFUs), many of which do not heal. Non-healing DFUs are a major cause of hospitalization, amputation, and increased morbidity. Understanding the underlying mechanisms of impaired healing in DFU is crucial for its management. Recent Advances: This review focuses on the recent advancements on macrophages and neutrophils in diabetic wounds and DFUs. In particular, we discuss diabetes-induced dysregulations and dysfunctions of macrophages and neutrophils. Critical Issues: It is well established that diabetic wounds are characterized by stalled inflammation that results in impaired healing. Recent findings in the field suggest that dysregulation of macrophages and neutrophils plays a critical role in impaired healing in DFUs. The delineation of mechanisms that restore macrophage and neutrophil function in diabetic wound healing is the focus of intense investigation. Future Directions: The breadth of recently generated knowledge on the activity of macrophages and neutrophils in diabetic wound healing is impressive. Experimental models have delineated pathways that hold promise for the treatment of diabetic wounds and DFUs. These pathways may be useful targets for further clinical investigation.

Cardiac mononuclear phagocytic cells (Cardiac MPCs) participate in maintaining homeostasis and orchestrating cardiac responses upon injury. However, the function of specific MPC subtypes and the related cell fate commitment mechanisms remain elusive in regenerative and nonregenerative hearts due to their cellular heterogeneities. Using spatiotemporal single-cell epigenomic analysis of cardiac MPCs in regenerative (P1) and nonregenerative (P10) mouse hearts after injury, we found that P1 hearts accumulate reparative Arg1+ macrophages, while proinflammatory S100a9+Ly6c+ monocytes are uniquely abundant during nonregenerative remodeling. Moreover, blocking chemokine CXCR2 to inhibit the specification of the S100a9+Ly6c+-biased inflammatory fate in P10 hearts resulted in elevated wound repair responses and marked improvements in cardiac function after injury. Single-cell RNA-Seq further confirmed an increased Arg1+ macrophage subpopulation after CXCR2 blockade, which was accomplished by increased expression of wound repair-related genes and reduced expression of proinflammatory genes. Collectively, our findings provide instructive insights into the molecular mechanisms underlying the function and fate specification of heterogeneous MPCs during cardiac repair and identify potential therapeutic targets for myocardial infarction.

Impaired wound healing is one of the main clinical complications of type 2 diabetes (T2D) and a major cause of lower limb amputation. Diabetic wounds exhibit a sustained inflammatory state, and reducing inflammation is crucial to diabetic wounds management. Macrophages are key regulators in wound healing, and their dysfunction would cause exacerbated inflammation and poor healing in diabetic wounds. Gene regulation caused by histone modifications can affect macrophage phenotype and function during diabetic wound healing. Recent studies have revealed that targeting histone-modifying enzymes in a local, macrophage-specific manner can reduce inflammatory responses and improve diabetic wound healing. This article will review the significance of macrophage phenotype and function in wound healing, as well as illustrate how histone modifications affect macrophage polarization in diabetic wounds. Targeting macrophage phenotype with histone-modifying enzymes may provide novel therapeutic strategies for the treatment of diabetic wound healing., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Wang, Feng, Ni, Wang, Zhang, Cao, Zhou and Zhao.)

The skin, being the body's largest organ, primarily functions as a formidable defense mechanism against potential microbial infections. The skin's microbiota, consisting of a complex assembly of microorganisms, exerts a pivotal influence on skin homeostasis by modulating keratinocytes and their cytokine secretion, thereby playing an integral role in promoting optimal cutaneous health. Leuconostoc mesenteroides finds extensive application in the production of fermented foods and bacteriocins. Empirical studies validate the effectiveness of L. mesenteroides treatments in enhancing immune function and demonstrating notable antioxidant characteristics. This study investigates the potential of L. mesenteroides in improving skin health and wound healing. It also aims to comprehend their impact on wound healing markers, cytokine production, and cell cycle regulation compared to ferulic acid, known for its wound healing effects. Our findings indicate that L. mesenteroides lysate possesses antibacterial properties against Staphylococcus aureus and Pseudomonas aeruginosa, along with the ability to mitigate their toxic effects in a pathogen-simulating model employing HaCaT keratinocyte cells. Additionally, the lysate demonstrated noteworthy wound closure after a 24-hour treatment, along with a significant reduction in interleukin-6 levels and oxidative stress index. Modulation of the cell cycle is evident by decreasing G0/G1 phases and increasing S and G2/M phases and enhanced expression of wound healing marker genes and proteins CDH1. In conclusion, L. mesenteroides lysate exhibits immune-modulating and antibacterial properties, offering potential alternatives to conventional treatments for various skin conditions. These findings contribute to the exploration of innovative approaches to enhancing human life through skin health and wound healing., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Monocytes and macrophages (Mos/Mϕs) play diverse roles in wound healing by adopting a spectrum of functional phenotypes; however, the regulation of such heterogeneity remains poorly defined. We enhanced our previously published Bayesian inference TF activity model, incorporating both single-cell RNA sequencing and single-cell ATAC sequencing data to infer transcription factor (TF) activity in Mos/Mϕs during skin wound healing. We found that wound Mos/Mϕs clustered into early-stage Mos/Mϕs, late-stage Mϕs, and APCs, and that each cluster showed differential chromatin accessibility and differential predicted TF activity that did not always correlate with mRNA or protein expression. Network analysis revealed two highly connected large communities involving a total of 19 TFs, highlighting TF cooperation in regulating wound Mos/Mϕs. This analysis also revealed a small community populated by NR4A1 and NFKB1, supporting a proinflammatory link between these TFs. Importantly, we validated a proinflammatory role for NR4A1 activity during wound healing, showing that Nr4a1 knockout mice exhibit decreased inflammatory gene expression in early-stage wound Mos/Mϕs, along with delayed wound re-epithelialization and impaired granulation tissue formation. In summary, our study provides insight into TF activity that regulates Mo/Mϕ heterogeneity during wound healing and provides a rational basis for targeting Mo/Mϕ TF networks to alter phenotypes and improve healing., (Copyright © 2024 by The American Association of Immunologists, Inc.)

Mucosa-associated invariant T (MAIT) cells are a subset of innate-like non-conventional T cells characterized by multifunctionality. In addition to their well-recognized antimicrobial activity, increasing attention is being drawn towards their roles in tissue homeostasis and repair. However, the precise mechanisms underlying these functions remain incompletely understood and are still subject to ongoing exploration. Currently, it appears that the tissue localization of MAIT cells and the nature of the diseases or stimuli, whether acute or chronic, may induce a dynamic interplay between their pro-inflammatory and anti-inflammatory, or pathogenic and reparative functions. Therefore, elucidating the conditions and mechanisms of MAIT cells' reparative functions is crucial for fully maximizing their protective effects and advancing future MAIT-related therapies. In this review, we will comprehensively discuss the establishment and potential mechanisms of their tissue repair functions as well as the translational application prospects and current challenges in this field., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Gao and Zhao.)

In this article for the Highlights of 2023 Series, we discuss recent research on unconventional T cells with a focus on gamma delta T cell development and cancer cell targeting, as well as the contributions of MAIT cells to wound repair., (© 2024 the Australian and New Zealand Society for Immunology, Inc.)

Chronic non-healing wounds persist as a substantial burden for healthcare systems, influenced by factors such as aging, diabetes, and obesity. In contrast to the traditionally pro-regenerative emphasis of therapies, the recognition of the immune system integral role in wound healing has significantly grown, instigating an approach shift towards immunological processes. Thus, this review explores the wound healing process, highlighting the engagement of the immune system, and delving into the behaviors of innate and adaptive immune cells in chronic wound scenarios. Moreover, the article investigates biomaterial-based strategies for the modulation of the immune system, elucidating how the adjustment of their physicochemical properties or their synergistic combination with other agents such as drugs, proteins or mesenchymal stromal cells can effectively modulate the behaviors of different immune cells. Finally this review explores various strategies based on synthetic and biological nanostructures, including extracellular vesicles, to finely tune the immune system as natural immunomodulators or therapeutic nanocarriers with promising biophysical properties., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.)

Plasmacytoid dendritic cells (pDCs) are first responders to tissue injury, where they prime naive T cells. The role of pDCs in physiologic wound repair has been examined, but little is known about pDCs in diabetic wound tissue and their interactions with naive CD4+ T cells. Diabetic wounds are characterized by increased levels of inflammatory IL-17A cytokine, partly due to increased Th17 CD4+ cells. This increased IL-17A cytokine, in excess, impairs tissue repair. Here, using human tissue and murine wound healing models, we found that diabetic wound pDCs produced excess IL-6 and TGF-β and that these cytokines skewed naive CD4+ T cells toward a Th17 inflammatory phenotype following cutaneous injury. Further, we identified that increased IL-6 cytokine production by diabetic wound pDCs is regulated by a histone demethylase, Jumonji AT-rich interactive domain 1C histone demethylase (JARID1C). Decreased JARID1C increased IL-6 transcription in diabetic pDCs, and this process was regulated upstream by an IFN-I/TYK2/JAK1,3 signaling pathway. When inhibited in nondiabetic wound pDCs, JARID1C skewed naive CD4+ T cells toward a Th17 phenotype and increased IL-17A production. Together, this suggests that diabetic wound pDCs are epigenetically altered to increase IL-6 expression that then affects T cell phenotype. These findings identify a therapeutically manipulable pathway in diabetic wounds.

Regulatory T (Treg) cells are classically known for their critical immunosuppressive functions that support peripheral tolerance. More recent work has demonstrated that Treg cells produce pro-repair mediators independent of their immunosuppressive function, a process that is critical to repair and regeneration in response to numerous tissue insults. These factors act on resident parenchymal and structural cells to initiate repair in a tissue-specific context. This review examines interactions between Treg cells and tissue-resident non-immune cells-in the context of tissue repair, fibrosis, and cancer-and discusses areas for future exploration., (© 2024 Loffredo et al.)

The interplay between bacteria and their host influences the homeostasis of the human immune microenvironment, and this reciprocal interaction also affects the process of tissue damage repair. A variety of immunomodulatory commensal bacteria reside in the body, capable of delivering membrane vesicles (MVs) to host cells to regulate the local immune microenvironment. This research revealed, for the initial time, the significant enhancement of mucosal and cutaneous wound healing by MVs secreted by the human commensal Lactobacillus reuteri (RMVs) through modulation of the inflammatory environment in wound tissue. Local administration of RMVs reduces the proportion of pro-inflammatory macrophages in inflamed tissues and mitigates the level of local inflammation, thereby facilitating the healing of oral mucosa and cutaneous wounds. The elevated oxidative stress levels in activated pro-inflammatory macrophages can be modulated by RMVs, resulting in phenotypic transformation of macrophages. Furthermore, 3-hydroxypropionaldehyde present in RMVs can decrease the mitochondrial permeability of macrophages and stabilize the mitochondrial membrane potential, thereby promoting the conversion of macrophages to an anti-inflammatory phenotype. This study pioneers the significance of commensal bacterial MVs in tissue injury repair and presents a novel concept for the repair of tissue damage., (© 2024 The Authors. Advanced Science published by Wiley‐VCH GmbH.)

IL-17 is widely recognized for its roles in host defense and inflammatory disorders. However, it has become clear that IL-17 is also an essential regulator of barrier tissue physiology. Steady-state microbe sensing at the skin surface induces low-level IL-17 expression that enhances epithelial integrity and resists pathogens without causing overt inflammation. Recent reports describe novel protective roles for IL-17 in wound healing and counteracting physiologic stress; however, chronic amplification of these beneficial responses contributes to skin pathologies as diverse as fibrosis, cancer, and autoinflammation. In this paper, we discuss the context-specific roles of IL-17 in skin health and disease and therapeutic opportunities., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Fibroblasts are ubiquitous mesenchymal cells that exhibit considerable molecular and functional heterogeneity. Besides maintaining stromal integrity, oral fibroblast subsets are thought to play an important role in host-microbe interaction during injury repair, which is not well explored in vivo. Here, we characterize a subset of fibroblast lineage labeled by paired-related homeobox-1 promoter activity (Prx1Cre + ) in oral mucosa and skin and demonstrate these fibroblasts readily respond to microbial products to facilitate the normal wound healing process. Using a reporter mouse model, we determined that Prx1Cre + fibroblasts had significantly higher expression of toll-like receptors 2 and 4 compared to other fibroblast populations. In addition, Prx1 immunopositive cells exhibited heightened activation of inflammatory transcription factor NF-κB during the early wound healing process. At the cytokine level, CXCL1 and CCL2 were significantly upregulated by Prx1Cre + fibroblasts at baseline and upon LPS stimulation. Importantly, lineage-specific knockout to prevent NF-κB activation in Prx1Cre + fibroblasts drastically impaired both oral and skin wound healing processes, which was linked to reduced macrophage infiltration, failure to resolve inflammation, and clearance of bacteria. Together, our data implicate a pro-healing role of Prx1-lineage fibroblasts by facilitating early macrophage recruitment and bacterial clearance., (© 2023 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Stem cells heal wounds. In this issue of Immunity, Luan et al. demonstrate that epidermal stem cells orchestrate the recruitment of regulatory T (Treg) cells and neutrophils during wound healing. Treg cells facilitate a tolerogenic environment to protect epithelial regeneration while neutrophils promote inflammation to ward off infection., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Following tissue damage, epithelial stem cells (SCs) are mobilized to enter the wound, where they confront harsh inflammatory environments that can impede their ability to repair the injury. Here, we investigated the mechanisms that protect skin SCs within this inflammatory environment. Characterization of gene expression profiles of hair follicle SCs (HFSCs) that migrated into the wound site revealed activation of an immune-modulatory program, including expression of CD80, major histocompatibility complex class II (MHCII), and CXC motif chemokine ligand 5 (CXCL5). Deletion of CD80 in HFSCs impaired re-epithelialization, reduced accumulation of peripherally generated Treg (pTreg) cells, and increased infiltration of neutrophils in wounded skin. Importantly, similar wound healing defects were also observed in mice lacking pTreg cells. Our findings suggest that upon skin injury, HFSCs establish a temporary protective network by promoting local expansion of Treg cells, thereby enabling re-epithelialization while still kindling inflammation outside this niche until the barrier is restored., Competing Interests: Declaration of interests E.F. is on the editorial board of some Elsevier Journals (Cell, Cell Stem Cell, and Developmental Cell). A.Y.R. is a member of SAB and has equity in Coherus, RAPT Therapeutics, Sonoma Biotherapeutics, Santa Ana Bio, and Vedanta Biosciences; is an SAB member of BioInvent and Amgen; and holds a therapeutic Treg cell depletion IP licensed to Takeda., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

The rational design of hydrogel materials to modulate the immune microenvironment has emerged as a pivotal approach in expediting tissue repair and regeneration. Within the immune microenvironment, an array of immune cells exists, with macrophages gaining prominence in the field of tissue repair and regeneration due to their roles in cytokine regulation to promote regeneration, maintain tissue homeostasis, and facilitate repair. Macrophages can be categorized into two types: classically activated M1 (pro-inflammatory) and alternatively activated M2 (anti-inflammatory and pro-repair). By regulating the physical and chemical properties of hydrogels, the phenotypic transformation and cell behavior of macrophages can be effectively controlled, thereby promoting tissue regeneration and repair. A full understanding of the interaction between hydrogels and macrophages can provide new ideas and methods for future tissue engineering and clinical treatment. Therefore, this paper reviews the effects of hydrogel components, hardness, pore size, and surface morphology on cell behaviors such as macrophage proliferation, migration, and phenotypic polarization, and explores the application of hydrogels based on macrophage immune regulation in skin, bone, cartilage, and nerve tissue repair. Finally, the challenges and future prospects of macrophage-based immunomodulatory hydrogels are discussed., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Given the self-evident importance of cutaneous immunity in the maintenance of body-surface homeostasis, disturbance of the steady-state skin is inextricably intertwined with dysfunction in cutaneous immunity. It is often overlooked by people that skin, well-known as a solid physical barrier, is also a strong immunological barrier, considering the abundant presence of immune cells including lymphocytes, granulocytes, dendritic cells, and macrophages. What's more, humoral immune components including cytokines, immunoglobulins, and antimicrobial peptides are also rich in the skin. This review centers on skin inflammation (acute and chronic, infection and aseptic inflammation), wound healing, and skin cancer to elucidate the elaborate network of immune cells in skin diseases., Competing Interests: Conflict of interest statement. None declared., (© The Author(s) 2023. Published by Oxford University Press on behalf of Society for Leukocyte Biology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Macrophages are the main cells shaping the local microenvironment during wound healing. As the prime T cells in the skin, γδ T cells participate in regulating microenvironment construction, determining their mutual regulation helps to understand the mechanisms of wound healing, and explore innovative therapeutic options for wound repair. This review introduced their respective role in wound healing firstly, and then summarized the regulatory effect of γδ T cells on macrophages, including chemotaxis, polarization, apoptosis, and pyroptosis. Last, the retrograde regulation on γδ T cells by macrophages was also discussed. The main purpose is to excavate novel interventions for treating wound and provide new thought for further research., Competing Interests: Conflicts of interest: The authors report no conflicts of competing interest in this work., (© The Author(s) 2023. Published by Oxford University Press on behalf of Society for Leukocyte Biology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

The immune system has a critical role in orchestrating tissue healing. As a result, regenerative strategies that control immune components have proved effective 1,2 . This is particularly relevant when immune dysregulation that results from conditions such as diabetes or advanced age impairs tissue healing following injury 2,3 . Nociceptive sensory neurons have a crucial role as immunoregulators and exert both protective and harmful effects depending on the context 4-12 . However, how neuro-immune interactions affect tissue repair and regeneration following acute injury is unclear. Here we show that ablation of the Na V 1.8 nociceptor impairs skin wound repair and muscle regeneration after acute tissue injury. Nociceptor endings grow into injured skin and muscle tissues and signal to immune cells through the neuropeptide calcitonin gene-related peptide (CGRP) during the healing process. CGRP acts via receptor activity-modifying protein 1 (RAMP1) on neutrophils, monocytes and macrophages to inhibit recruitment, accelerate death, enhance efferocytosis and polarize macrophages towards a pro-repair phenotype. The effects of CGRP on neutrophils and macrophages are mediated via thrombospondin-1 release and its subsequent autocrine and/or paracrine effects. In mice without nociceptors and diabetic mice with peripheral neuropathies, delivery of an engineered version of CGRP accelerated wound healing and promoted muscle regeneration. Harnessing neuro-immune interactions has potential to treat non-healing tissues in which dysregulated neuro-immune interactions impair tissue healing., (© 2024. The Author(s).)

Diabetic foot ulcers (DFUs) are one of the most common and challenging complications of diabetes, yet our understanding of their pathogenesis remains limited. We collected gene expression data of DFU patients from public databases. Bioinformatics tools were applied for systematic analysis, including the identification of differentially expressed genes (DEGs), weighted gene co-expression network analysis (WGCNA) and enrichment analysis. We further used single-cell RNA sequencing to identify the distribution of different cell populations in DFU. Finally, key results were validated using reverse transcription-quantitative polymerase chain reaction (RT-qPCR) and flow cytometry. We identified 217 DEGs between ulcerated and healthy skin, and 37 DEGs between healing ulcers and ulcers. WGCNA revealed that the cyan module had the highest positive correlation with healthy skin and negative correlation with ulcers. The black module had the highest negative correlation with healthy skin and positive correlation with ulcers. Enrichment analysis showed that the genes in the cyan module were mainly associated with complement and coagulation cascades, while the genes in the black module were mainly associated with the IL-17 signalling pathway. In addition, CD8 T cells were significantly lower in ulcers than in healthy and healing ulcers. By comparing marker genes of CD8 T cells, we identified key genes in the cyan and black modules and validated their expression using RT-qPCR. The proportion of CD8 T cells was increased in healing ulcers. Flow cytometry detected increased levels of CD8 T, B and natural killer cells in healing ulcers. CD8 T cells and related key genes play an important role in the healing process of DFU. The results of this study provide a new perspective for understanding the pathogenesis and treatment of DFU., (© 2023 The Authors. International Wound Journal published by Medicalhelplines.com Inc and John Wiley & Sons Ltd.)

Monocytes/macrophages are pivotal in host defense, inflammation, and tissue repair. They are actively engaged during helminth infections, playing critical roles in trapping pathogens, eliminating them, repairing tissue damage, and mitigating type 2 inflammation. These cells are indispensable in preserving physiological equilibrium and overseeing pathogen resistance as well as metabolic processes. Furthermore, these immune cells are influenced by cellular metabolism, which adjusts in response to host-derived factors and environmental cues. They secrete effector molecules crucial for anti-helminthic immunity and healing tissues damaged by parasites. Helminth parasites manipulate the immune regulatory capabilities of monocytes/macrophages by secreting anti-inflammatory mediators to dodge host defenses. Infections, especially with helminths, induce metabolic adaptations involving monocytes/macrophages that can lead to enhanced insulin sensitivity. This review provides a synthesis of the activation and diversity of monocytes/macrophages, their involvement in inflammation, and the latest insights into the strategies of monocyte/macrophage-mediated host defense against helminth infections. It also sheds light on recent discoveries concerning the immune regulatory interactions between monocytes/macrophages and helminth parasites., (© 2024. The Author(s), under exclusive license to Springer Nature Switzerland AG.)

Pathological scars are the result of over-repair and excessive tissue proliferation of the skin injury. It may cause serious dysfunction, resulting in psychological and physiological burdens on the patients. Currently, mesenchymal stem cells-derived exosomes (MSC-Exo) displayed a promising therapeutic effect on wound repair and scar attenuation. But the regulatory mechanisms are opinions vary. In view of inflammation has long been proven as the initial factor of wound healing and scarring, and the unique immunomodulation mechanism of MSC-Exo, the utilization of MSC-Exo may be promising therapeutic for pathological scars. However, different immune cells function differently during wound repair and scar formation. The immunoregulatory mechanism of MSC-Exo would differ among different immune cells and molecules. Herein, this review gave a comprehensive summary of MSC-Exo immunomodulating different immune cells in wound healing and scar formation to provide basic theoretical references and therapeutic exploration of inflammatory wound healing and pathological scars., Competing Interests: The authors report no conflicts of interest in this work., (© 2023 Zhao et al.)

Background: Closing mucosal defects to reach mucosal healing is an important goal of therapy in inflammatory bowel disease (IBD). Among other cells, monocyte-derived macrophages are centrally involved in such intestinal wound healing. We had previously demonstrated that the anti-α4β7 integrin antibody vedolizumab blocks the recruitment of non-classical monocytes as biased progenitors of wound healing macrophages to the gut and delays wound healing. However, although important for the interpretation of disappointing results in recent phase III trials in IBD, the effects of the anti-β7 antibody etrolizumab on wound healing are unclear so far., Methods: We analyzed the expression of etrolizumab targets on human and mouse monocyte subsets by flow cytometry and assessed their function in adhesion and homing assays. We explored wound-associated monocyte recruitment dynamics with multi-photon microscopy and compared the effects of etrolizumab and vedolizumab surrogate (-s) antibodies on experimental wound healing and wound-associated macrophage abundance. Finally, we investigated wound healing macrophage signatures in the large intestinal transcriptome of patients with Crohn's disease treated with etrolizumab., Results: Human and mouse non-classical monocytes expressed more αEβ7 integrin than classical monocytes and were a target of etrolizumab-s, which blocked non-classical monocyte adhesion to MAdCAM-1 and E-Cadherin as well as gut homing in vivo. Intestinal wound healing was delayed on treatment with etrolizumab-s along with a reduction of peri-lesional wound healing macrophages. Wound healing macrophage signatures in the colon of patients with Crohn's disease were substantially down-regulated on treatment with etrolizumab, but not with placebo., Conclusions: Combined blockade of αEβ7 and α4β7 with etrolizumab seems to exceed the effect of anti-α4β7 treatment on intestinal wound healing, which might help to inform further investigations to understand the recent observations in the etrolizumab phase III trial program., (© 2023 The Authors. Clinical and Translational Medicine published by John Wiley & Sons Australia, Ltd on behalf of Shanghai Institute of Clinical Bioinformatics.)

Background: Skin aging arises from immunological responses to tissue deterioration and damage. Tissue repair processes encompass the regeneration of original tissue and 'scarless' wound healing seen in foetuses, and the extreme fibrotic responses and scarring seen in adults. Anti-aging aesthetic medicine uses interventions like biomaterial-based fillers to influence these immunological responses and renew aged tissue structure and function. At filler injection sites, an inflammatory response occurs that causes a spectrum of outcomes, ranging from tissue regeneration to fibrosis and filler encapsulation. Importantly, the resulting inflammatory pathway can be predetermined by the biomaterial injected., Aims: By understanding this immunological process, we can develop Aesthetic Regenerative Scaffolds (ARS) - aesthetic injectable biomaterials - to direct inflammatory wound healing away from chronic, fibrotic responses, and towards physiological tissue regeneration., Materials and Methods: We identified and reviewed literature on the immunological and cellular responses to injected dermal fillers, whereby the wound healing response to the injection was moderated under the influence of an injected biomaterial., Results: We described the mechanisms of dermal wound healing and the use of ARS to direct healing towards tissue regeneration instead of scarring. We also summarised studies on extracellular matrix remodeling by calcium hydroxylapatite. We found that Calcium hydroxylapatite fillers produce collagen as they gradually degrade and their spherical structures serve as a scaffold for tissue regeneration. Furthermore, CaHA improved fibroblast contractility, collagen type III and elastin production, proliferation and angiogenesis with less inflammation than hyaluronic acid fillers., Discussion: Regneration pathways can be influenced at specific points between a facial filler biomaterial and the wound healingmechanisms at its site of implantaion., Conclusion: Physicians can select scaffolds that direct the immune response away from a fibrotic chronic inflammatory pathway and towards regeneration to enable true repair of the aging skin., (© 2023 The Author. Journal of Cosmetic Dermatology published by Wiley Periodicals LLC.)

Fish skin is a multifunctional tissue that develops during embryogenesis, a developmental stage highly susceptible to epigenetic marks. In this study, the impact of egg incubation temperature on the regeneration of a cutaneous wound caused by scale removal in juvenile European sea bass was evaluated. Sea bass eggs were incubated at 11, 13.5 and 16 °C until hatching and then were reared at a common temperature until 9 months when the skin was damaged and sampled at 0, 1 and 3 days after scale removal and compared to the intact skin from the other flank. Skin damage elicited an immediate significant (p < 0.001) up-regulation of pcna in fish from eggs incubated at higher temperatures. In fish from eggs incubated at 11 °C there was a significant (p < 0.001) up-regulation of krt2 compared to fish from higher thermal backgrounds 1 day after skin damage. Damaged epidermis was regenerated after 3 days in all fish irrespective of the thermal background, but in fish from eggs incubated at 11 °C the epidermis was significantly (p < 0.01) thinner compared to other groups, had less goblet cells and less melanomacrophages. The thickness of the dermis increased during regeneration of wounded skin irrespective of the thermal background and by 3 days was significantly (p < 0.01) thicker than the dermis from the intact flank. The expression of genes for ECM remodelling (mmp9, colXα, col1α1, sparc, and angptl2b) and innate immunity (lyg1, lalba, sod1, csf-1r and pparγ) changed during regeneration but were not affected by egg thermal regime. Overall, the results indicate that thermal imprinting of eggs modifies the damage-repair response in juvenile sea bass skin., Competing Interests: Declarations of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Intestinal epithelial integrity is commonly disrupted in patients with critical disorders, but the exact underlying mechanisms are unclear. Long noncoding RNAs transcribed from ultraconserved regions (T-UCRs) control different cell functions and are involved in pathologies. Here, we investigated the role of T-UCRs in intestinal epithelial homeostasis and identified T-UCR uc.230 as a major regulator of epithelial renewal, apoptosis, and barrier function. Compared with controls, intestinal mucosal tissues from patients with ulcerative colitis and from mice with colitis or fasted for 48 hours had increased levels of uc.230. Silencing uc.230 inhibited the growth of intestinal epithelial cells (IECs) and organoids and caused epithelial barrier dysfunction. Silencing uc.230 also increased IEC vulnerability to apoptosis, whereas increasing uc.230 levels protected IECs against cell death. In mice with colitis, reduced uc.230 levels enhanced mucosal inflammatory injury and delayed recovery. Mechanistic studies revealed that uc.230 increased CUG-binding protein 1 (CUGBP1) by acting as a natural decoy RNA for miR-503, which interacts with Cugbp1 mRNA and represses its translation. These findings indicate that uc.230 sustains intestinal mucosal homeostasis by promoting epithelial renewal and barrier function and that it protects IECs against apoptosis by serving as a natural sponge for miR-503, thereby preserving CUGBP1 expression.

Mammalian cells autonomously activate hypoxia-inducible transcription factors (HIFs) to ensure survival in low-oxygen environments. We report here that injury-induced hypoxia is insufficient to trigger HIF1α in damaged epithelium. Instead, multimodal single-cell and spatial transcriptomics analyses and functional studies reveal that retinoic acid-related orphan receptor γt + (RORγt + ) γδ T cell-derived interleukin-17A (IL-17A) is necessary and sufficient to activate HIF1α. Protein kinase B (AKT) and extracellular signal-regulated kinase 1/2 (ERK1/2) signaling proximal of IL-17 receptor C (IL-17RC) activates mammalian target of rapamycin (mTOR) and consequently HIF1α. The IL-17A-HIF1α axis drives glycolysis in wound front epithelia. Epithelial-specific loss of IL-17RC, HIF1α, or blockade of glycolysis derails repair. Our findings underscore the coupling of inflammatory, metabolic, and migratory programs to expedite epithelial healing and illuminate the immune cell-derived inputs in cellular adaptation to hypoxic stress during repair.

Human skin forms a protective barrier against the external environment and is our first line of defense against toxic, solar, and pathogenic insults. Our skin also defines our outward appearance, protects our internal tissues and organs, acts as a sensory interface, and prevents dehydration. Crucial to the skin's barrier function is the colonizing microbiota, which provides protection against pathogens, tunes immune responses, and fortifies the epithelium. Here we highlight recent advances in our understanding of how the microbiota mediates multiple facets of skin barrier function. We discuss recent insights into pathological host-microbiota interactions and implications for disorders of the skin and distant organs. Finally, we examine how microbiota-based mechanisms can be targeted to prevent or manage skin disorders and impaired wound healing.

Infection is a major co-morbidity that contributes to impaired healing in diabetic wounds. Although impairments in diabetic neutrophils have been blamed for this co-morbidity, what causes these impairments and whether they can be overcome, remain largely unclear. Diabetic neutrophils, isolated from diabetic individuals, exhibit chemotaxis impairment but this peculiar functional impairment has been largely ignored because it appears to contradict the clinical findings which blame excessive neutrophil influx as a major impediment to healing in chronic diabetic ulcers. Here, we report that exposure to glucose in diabetic range results in impaired chemotaxis signaling through the formyl peptide receptor (FPR) in neutrophils, culminating in reduced chemotaxis and delayed neutrophil trafficking in the wound of Lepr db (db/db) type two diabetic mice, rendering diabetic wound vulnerable to infection. We further show that at least some auxiliary receptors remain functional under diabetic conditions and their engagement by the pro-inflammatory cytokine CCL3, overrides the requirement for FPR signaling and substantially improves infection control by jumpstarting the neutrophil trafficking toward infection, and stimulates healing in diabetic wound. We posit that CCL3 may have therapeutic potential for the treatment of diabetic foot ulcers if it is applied topically after the surgical debridement process which is intended to reset chronic ulcers into acute fresh wounds., Competing Interests: RR, JZ, SS, KD, SW, MM, DF, YA, TP, RE, EG, TK, AZ, JR No competing interests declared, SS Rush University Medical Center has filed a patent (International Application Number: PCT/US19/41112). Dr. Sasha Shafikhani is the listed inventor on this application, (© 2022, Roy et al.)

Chronic inflammation is often associated with the development of tissue fibrosis, but how mesenchymal cell responses dictate pathological fibrosis versus resolution and healing remains unclear. Defining stromal heterogeneity and identifying molecular circuits driving extracellular matrix deposition and remodeling stands to illuminate the relationship between inflammation, fibrosis, and healing. We performed single-cell RNA-sequencing of colon-derived stromal cells and identified distinct classes of fibroblasts with gene signatures that are differentially regulated by chronic inflammation, including IL-11-producing inflammatory fibroblasts. We further identify a transcriptional program associated with trans-differentiation of mucosa-associated fibroblasts and define a functional gene signature associated with matrix deposition and remodeling in the inflamed colon. Our analysis supports a critical role for the metalloprotease Adamdec1 at the interface between tissue remodeling and healing during colitis, demonstrating its requirement for colon epithelial integrity. These findings provide mechanistic insight into how inflammation perturbs stromal cell behaviors to drive fibroblastic responses controlling mucosal matrix remodeling and healing., Competing Interests: I have read the journal’s policy and the authors of this manuscript have the following competing interests: R.J.X. is a cofounder of Celsius Therapeutics and Jnana Therapeutics.

Type 2 immunity, illustrated by T helper 2 lymphocytes (Th2) and downstream cytokines (IL-4, IL-13, IL-31) as well as group 2 innate lymphoid cells (ILC2), is important in host defense and wound healing. 1 The hallmark of type 2 inflammation is eosinophilia and/or high IgE counts and is best recognized in atopic diathesis. Persistent eosinophilia, such as seen in hypereosinophilic syndromes, leads to fibrosis and hence therapeutic Type 2 inhibition in fibrotic diseases is of high interest. Furthermore, as demonstrated in cutaneous T cell lymphoma, advanced disease is characterized by Th1 to Th2 switch allowing cancer progression and immunosuppression. Development of targeted monoclonal antibodies against IL-4Rα (eg, dupilumab) led to a paradigm shift for the treatment of atopic dermatitis (AD) and stimulated research to better understand the role of Type 2 inflammation in other skin conditions. In this review, we summarize up to date knowledge on the role of Type 2 inflammation in skin diseases other than AD and highlight whether the use of Type 2 targeted therapies has been documented or is being investigated in clinical trials. This manuscript reviews the role of Type 2 inflammation in dermatitis, neurodermatitis, IgE-mediated dermatoses (eg, bullous pemphigoid, chronic spontaneous urticaria), sclerodermoid conditions and skin neoplasms.

Background: Serum globulin is an inflammation marker. To date, no evidence regarding the association between serum globulin and disease activity in patients with ulcerative colitis has been reported., Aims: We evaluated the association between serum globulin and endoscopic activity in patients with ulcerative colitis., Methods: Serum globulin was divided into tertiles based on the distribution of study subjects (low globulin, ≤ 2.7 g/dl (reference); moderate globulin, 2.7-3.1 g/dl; and high globulin, > 3.1 g/dl). A single endoscopic specialist evaluated the endoscopic findings, and mucosal healing was based on Mayo endoscopic subscore., Results: A total of 277 patients with ulcerative colitis were included in the study. Serum globulin was independently positively associated with diminished or absent vascular markings [moderate: adjusted odds ratio (OR) 3.70 (95% confidence interval, CI: 1.82-7.88) and high: adjusted OR 2.40 (95%CI: 1.20-4.94), p for trend = 0.005]. A similar positive association between globulin and erosion was found [high: adjusted OR 2.00 (95%CI: 1.05-3.86)]. Serum globulin was independently inversely associated with mucosal healing [moderate: adjusted OR 0.37 (95%CI: 0.18-0.73) and high: adjusted OR 0.31 (95%CI: 0.14-0.64), p for trend = 0.001] and adjusted partial mucosal healing [moderate: OR 0.51 (95%CI: 0.26-0.98), p for trend = 0.048]. The inverse association between globulin and mucosal healing was significant in the low but not the high C-reactive protein group., Conclusions: In patients with ulcerative colitis, serum globulin was significantly positively associated with endoscopic activity, and was significantly inversely associated with mucosal healing, especially in the low C-reactive protein group., (© 2021. The Author(s), under exclusive licence to Springer Science+Business Media, LLC part of Springer Nature.)

Host inflammatory immune response comprises an essential element of the bone healing process, where M2 polarization allegedly contributes to a favorable healing outcome. In this context, immunoregulatory molecules that modulate host response, including macrophage polarization, are considered potential targets for improving bone healing. This study aims to evaluate the role of the immunoregulatory molecules VIP (Vasoactive intestinal peptide) and PACAP (Pituitary adenylate cyclase activating polypeptide), which was previously described to favor the development of the M2 phenotype, in the process of alveolar bone healing in C57Bl/6 (WT) mice. Experimental groups were submitted to tooth extraction and maintained under control conditions or treated with VIP or PACAP were evaluated by microtomographic (µCT), histomorphometric, immunohistochemical, and molecular analysis at 0, 3, 7, and 14 days to quantify tissue healing and host response indicators at the healing site. Gene expression analysis demonstrates the effectiveness of VIP or PACAP in modulating host response, evidenced by the early dominance of an M2-type response, which was paralleled by a significant increase in M2 (CD206 + ) in treated groups. However, despite the marked effect of M1/M2 balance in the healing sites, the histomorphometric analysis does not reveal an equivalent/corresponding modulation of the healing process. µCT reveals a slight increase in bone matrix volume and the trabecular thickness number in the PACAP group, while histomorphometric analyzes reveal a slight increase in the VIP group, both at a 14-d time-point; despite the increased expression of osteogenic factors, osteoblastic differentiation, activity, and maturation markers in both VIP and PACAP groups. Interestingly, a lower number of VIP and PACAP immunolabeled cells were observed in the treated groups, suggesting a reduction in endogenous production. In conclusion, while both VIP and PACAP treatments presented a significant immunomodulatory effect with potential for increased healing, no major changes were observed in bone healing outcome, suggesting that the signals required for bone healing under homeostatic conditions are already optimal, and additional signals do not improve an already optimal process. Further studies are required to elucidate the role of macrophage polarization in the bone healing process., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Azevedo, Fonseca, Colavite, Melchiades, Tabanez, Codo, de Medeiros, Trombone and Garlet.)

Composite tissue injuries (CTI) are common among US Military Service members during combat operations, and carry a high potential of morbidity. Furthermore, CTI are often complicated due to an altered wound healing response, resulting in part from a dysregulation of the innate and adaptive immune responses. Unlike normal wound healing, in CTI, disruptions occur in innate immune responses, altering neutrophil functions, macrophage activation and polarization, further impacting the functions of T regulatory cells. Additionally, the biological underpinnings of these unfavorable wound healing conditions are multifactorial, including various processes, such as: ischemia, hypoxia, low nutrient levels, and altered cell metabolic pathways, among others, all of which are thought to trigger anergy in immune cells and destabilize adaptive immune responses. As a result, impaired wound healing is common in CTI. Herein, we review the altered innate and adaptive immune cells and their metabolic status and responses following CTI, and discuss the role a multi-pronged immunomodulatory approach may play in facilitating improved outcomes for afflicted patients.

Impaired wound healing associated with recurrent Staphylococcus aureus infection and unresolved inflammation are hallmarks of nonhealing diabetic foot ulcers (DFUs). Perforin-2, an innate immunity molecule against intracellular bacteria, limits cutaneous infection and dissemination of S. aureus in mice. Here, we report the intracellular accumulation of S. aureus in the epidermis of DFUs with no clinical signs of infection due to marked suppression of perforin-2. S. aureus residing within the epidermis of DFUs triggers AIM2 inflammasome activation and pyroptosis. These findings were corroborated in mice lacking perforin-2. The effects of pyroptosis on DFU clinical outcomes were further elucidated in a 4-week longitudinal clinical study in patients with DFUs receiving standard care. Increased AIM2 inflammasome and ASC-pyroptosome coupled with induction of IL-1β were found in nonhealing DFUs compared with healing DFUs. Our findings revealed that perforin-2 suppression, intracellular S. aureus accumulation, and associated induction of pyroptosis contribute to healing inhibition and prolonged inflammation in patients with DFUs.

Cathelicidin is a family of antimicrobial peptides (AMPs) existing in vertebrates, which play multiple functions in host responses against environmental stresses. All cathelicidins identified to date are cationic, no anionic member with net negative charges has been reported. In the present study, a novel anionic cathelicidin (TK-CATH) with a net charge of -3 was identified from the skin of the salamander, T. kweichowensis. Unlike most other cathelicidin members, it didn't exhibit direct antimicrobial activity. However, it demonstrated strong anti-inflammatory activity. It effectively inhibited the LPS-induced pro-inflammatory cytokine gene expression and protein production in amphibian leukocytes and mouse macrophages by inhibiting the LPS-activated mitogen-activated protein kinase (MAPK) signaling pathways. Besides, TK-CATH showed potent wound healing activity. It could effectively induce the production of several cytokines, chemokines and growth factors relating to wound healing, promote the motility and proliferation of keratinocytes, and accelerate the skin wound healing in a mouse full-thickness wound model. These results imply that TK-CATH participates in both the inflammatory phase and new tissue formation phase of wound repair process. Meanwhile, TK-CATH exhibited weak but effective free radical scavenging activity and low cytotoxicity. All the results above indicate that TK-CATH is a multifunctional peptide in the skin of the salamander T. kweichowensis. It may play important roles in host immune responses against bacterial infection and skin wound repair., Competing Interests: Declaration of competing interest The authors declare that they have no conflict of interest., (Copyright © 2021 Elsevier B.V. and Société Française de Biochimie et Biologie Moléculaire (SFBBM). All rights reserved.)

Regulatory T cells (T regs ) are specific subtype of T cells that play a central role in sustaining self-antigen tolerance and restricting inflammatory tissue damage. More recently, additional direct functions of T regs in mammalian tissue repair have emerged, but the regenerative potential of T regs in non-mammalian vertebrates has not been explored despite the latter possessing a highly developed adaptive immune system. Why complex organs such as the caudal fin, heart, brain, spinal cord and retina regenerate in certain non-mammalian vertebrates, but not in mammals, is an interesting but unresolved question in the field of regenerative biology. Inflammation has traditionally been thought to be an impediment to regeneration due to the formation of scars. Regenerative decline in higher organisms has been speculated to be the evolutionary advent of adaptive immunity. Recent studies, however, have shown that the innate inflammatory response in non-mammalian organisms is required for organ regeneration. It has also been found that highly advanced adaptive immunity is no longer incompatible with regeneration and for that, T regs are important. Zebrafish regulatory T cells (zT regs ) migrate rapidly to the injury site in damaged organs, where they facilitate the proliferation of regeneration precursor cells by generating tissue-specific regenerative factors by a process distinct from the canonical anti-inflammatory pathway. We review both reparative and proregenerative roles of T regs in mammals and zebrafish, respectively, and also give an overview of the forkhead box protein 3 (FoxP3) -dependent immunosuppressive function of T regs in zebrafish, which makes it a useful model organism for future T reg biology and research., (© 2021 British Society for Immunology.)

Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Tissue damage induces immediate-early signals, activating Rho small GTPases to trigger actin polymerization essential for later wound repair. However, how tissue damage is sensed to activate Rho small GTPases locally remains elusive. Here, we found that wounding the C. elegans epidermis induces rapid relocalization of CDC-42 into plasma membrane-associated clusters, which subsequently recruits WASP/WSP-1 to trigger actin polymerization to close the wound. In addition, wounding induces a local transient increase and subsequent reduction of H 2 O 2 , which negatively regulates the clustering of CDC-42 and wound closure. CDC-42 CAAX motif-mediated prenylation and polybasic region-mediated cation-phospholipid interaction are both required for its clustering. Cysteine residues participate in intermolecular disulfide bonds to reduce membrane association and are required for negative regulation of CDC-42 clustering by H 2 O 2 . Collectively, our findings suggest that H 2 O 2 -regulated fine-tuning of CDC-42 localization can create a distinct biomolecular cluster that facilitates rapid epithelial wound repair after injury., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2021 The Author(s). Published by Elsevier Inc. All rights reserved.)

Competing Interests: AB is the founder and Scientific Director of Science of Skin. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.