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Infection induced inflammation impairs wound healing through IL-1β signaling.

ABSTRACT: Wound healing is impaired by infection; however, how microbe-induced inflammation modulates tissue repair remains unclear. We took advantage of the optical transparency of zebrafish and a genetically tractable microbe, Listeria monocytogenes, to probe the role of infection and inflammation in wound healing. Infection with bacteria engineered to activate the inflammasome, Lm-Pyro, induced persistent inflammation and impaired healing despite low bacterial burden. Inflammatory infections induced il1b expression and blocking IL-1R signaling partially rescued wound healing in the presence of persistent infection. We found a critical window of microbial clearance necessary to limit persistent inflammation and enable efficient wound repair. Taken together, our findings suggest that the dynamics of microbe-induced tissue inflammation impacts repair in complex tissue damage independent of bacterial load, with a critical early window for efficient tissue repair.

SUBMITTER: Shen S

PROVIDER: S-EPMC10993181 | biostudies-literature | 2024 Apr

REPOSITORIES: biostudies-literature

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Infection induced inflammation impairs wound healing through IL-1β signaling.

Shen Simone S Miskolci Veronika V Dewey Colin N CN Sauer John-Demian JD Huttenlocher Anna A

iScience 20240319 4

Wound healing is impaired by infection; however, how microbe-induced inflammation modulates tissue repair remains unclear. We took advantage of the optical transparency of zebrafish and a genetically tractable microbe, <i>Listeria monocytogenes</i>, to probe the role of infection and inflammation in wound healing. Infection with bacteria engineered to activate the inflammasome, Lm-Pyro, induced persistent inflammation and impaired healing despite low bacterial burden. Inflammatory infections ind ...[more]

PMID: 38577110

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Project description:Rationale: In obesity the fine-tuned balance of macrophage phenotypes is disturbed towards a dominance of pro-inflammatory macrophages resulting in exacerbation and persistence of inflammation and impaired tissue repair. However, the underlying mechanisms are still poorly understood. Methods: Impact of obesity on macrophage differentiation was studied in high fat diet induced obese and db/db mice during skin inflammation and wound repair, respectively. Mechanisms of S100A9-mediated effects on macrophage differentiation was studied on in vitro generated macrophages by genomic and proteomic approaches. The role of S100A9 on macrophage differentiation was investigated by pharmacological inhibition of S100A9 during skin inflammation and wound repair in obese and db/db mice. Results: We demonstrate an overexpression of S100A9 in conditions of obesity-associated disturbed macrophage differentiation in the skin. We show that saturated free fatty acids (SFA), which are increased in obesity, together with S100A9 induce TLR4 and inflammasome-dependent IL-1β release in macrophages which in turn amplifies S100A9 expression initiating a vicious cycle of sustained S100A9 overexpression in skin inflammation in obesity. We reveal a yet unrecognized impact of obesity-associated S100A9 overexpression on macrophage differentiation. S100A9 binding to TLR4 and activation of NFkB attenuates development of M2-like macrophages and induces pro-inflammatory functions in these cells. Consequently, inhibition of S100A9 restores disturbed M2-like macrophage differentiation in mouse models of obesity-associated skin inflammation and wound repair. Similarly, breaking the vicious cycle of S100A9 overexpression by dietary reduction of SFA restored M2-like macrophage activation. Improvement of skin inflammation and wound repair upon reduction of S100A9 by pharmacological inhibition or by reduction of SFA uncovers the pathogenic role of S100A9 overexpression in obesity. Conclusion: This study identifies S100A9 as a previously unrecognized vital component in obesity-associated disturbed macrophage differentiation and subsequent impaired regulation of inflammation and wound repair. The findings open new opportunities for therapeutic implications for inflammatory diseases and wound repair in obesity.

Project description:Interleukin-1β (IL-1β) is one of the most potent pro-inflammatory cytokines implicated in a wide range of autoinflammatory, autoimmune, infectious, and degenerative diseases. Therefore, many researchers have focused on developing therapeutic molecules that inhibit IL-1β-IL-1 receptor 1 (IL-1R1) interaction for the treatment of IL-1-related diseases. Among IL-1-related diseases, osteoarthritis (OA), is characterized by progressive cartilage destruction, chondrocyte inflammation, and extracellular matrix (ECM) degradation. Tannic acid (TA) has been proposed to have multiple beneficial effects, including anti-inflammatory, anti-oxidant, and anti-tumor activities. However, it is unclear whether TA plays a role in anti-IL-1β activity by blocking IL-1β-IL-1R1 interaction in OA. In this study, we report the anti-IL-1β activity of TA in the progression of OA in both in vitro human OA chondrocytes and in vivo rat OA models. Herein, using-ELISA-based screening, natural compound candidates capable of inhibiting the IL-1β-IL-1R1 interaction were identified. Among selected candidates, TA showed hindering IL-1β-IL-1R1 interaction by direct binding to IL-1β using surface plasmon resonance (SPR) assay. In addition, TA inhibited IL-1β bioactivity in HEK-Blue IL-1-dependent reporter cell line. TA also inhibited IL-1β-induced expression of inducible nitric oxide synthase (NOS2), cyclooxygenase-2 (COX-2), IL-6, tumor necrosis factor-alpha (TNF-α), nitric oxide (NO), and prostaglandin E2 (PGE2) in human OA chondrocytes. Moreover, TA downregulated IL-1β-stimulated matrix metalloproteinase (MMP)3, MMP13, ADAM metallopeptidase with thrombospondin type 1 motif (ADAMTS)4, and ADAMTS5, while upregulating collagen type II (COL2A1) and aggrecan (ACAN). Mechanistically, we confirmed that TA suppressed IL-1β-induced MAPK and NF-κB activation. The protective effects of TA were also observed in a monosodium iodoacetamide (MIA)-induced rat OA model by reducing pain and cartilage degradation and inhibiting IL-1β-mediated inflammation. Collectively, our results provide evidence that TA plays a potential role in OA and IL-1β-related diseases by hindering IL-1β-IL-1R1 interaction and suppressing IL-1β bioactivity.

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Infection induced inflammation impairs wound healing through IL-1β signaling.

Publications

Infection induced inflammation impairs wound healing through IL-1β signaling.

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