Ending Inflammation and Restoring Tissue Homeostasis

The resolution of inflammation is a crucial phase that involves the active termination of the inflammatory response and the restoration of tissue homeostasis. Successful resolution prevents chronic inflammation, tissue damage, and excessive immune activation. Several key processes and negative feedback mechanisms contribute to the resolution of inflammation:

1. Anti-inflammatory Signals:
   • Production of Anti-inflammatory Cytokines:
     • Cells at the inflammatory site, including macrophages and regulatory T cells, produce anti-inflammatory cytokines such as interleukin-10 (IL-10).
     • IL-10 has suppressive effects on pro-inflammatory cytokine production and signaling.
2. Negative Feedback Mechanisms:
   • Inhibition of NF-κB:
     • NF-κB is a central transcription factor that regulates the expression of pro-inflammatory genes.
     • Negative feedback mechanisms, including the induction of inhibitors like IκB (inhibitor of NF-κB), terminate NF-κB signaling, limiting the production of pro-inflammatory cytokines.
   • Decoy Receptors:
     • Some cells release soluble or membrane-bound decoy receptors that bind to cytokines, preventing them from interacting with cell surface receptors.
     • For example, soluble receptors for tumor necrosis factor-alpha (sTNFR) act as decoys, inhibiting TNF-α signaling.
   • Deactivation of Inflammatory Mediators:
     • Enzymes like cyclooxygenase-2 (COX-2) and inducible nitric oxide synthase (iNOS), which contribute to the production of inflammatory mediators, are downregulated during resolution.
3. Clearance of Immune Cells:
   • Apoptosis and Efferocytosis:
     • Neutrophils, which are short-lived and highly reactive immune cells, undergo apoptosis (programmed cell death) at the inflammatory site.
     • Macrophages and other phagocytes recognize and engulf apoptotic cells in a process called efferocytosis.
     • Efferocytosis not only clears dying cells but also promotes the resolution of inflammation by dampening pro-inflammatory signals.
4. Specialized Pro-resolving Mediators (SPMs):
   • Resolvins, Lipoxins, and Protectins:
     • SPMs are lipid-derived mediators that actively promote the resolution of inflammation.
     • Resolvins, lipoxins, and protectins stimulate the clearance of apoptotic cells, limit the recruitment of new immune cells, and enhance tissue repair.
5. Transforming Growth Factor-beta (TGF-β):
   • Induction of TGF-β:
     • TGF-β is a multifunctional cytokine that plays a key role in tissue repair and resolution.
     • It inhibits inflammation, promotes tissue regeneration, and contributes to the suppression of immune responses.
6. Restoration of Tissue Homeostasis:
   • Tissue Repair and Remodeling:
     • Fibroblasts are activated to deposit extracellular matrix components, contributing to tissue repair and remodeling.
     • Growth factors released during resolution stimulate tissue regeneration.
7. Termination of Inflammatory Signals:
   • Resolution of Inflammatory Stimuli:
     • Removal or neutralization of the initial stimuli, such as pathogens or tissue-damaging agents, contributes to the termination of inflammation.
   • Downregulation of PRR Signaling:
     • Expression of PRRs on immune cells may be downregulated, reducing their responsiveness to PAMPs or DAMPs.
8. Return to Homeostasis:
   • Cessation of Immune Cell Infiltration:
     • Chemokine signals that attract immune cells are downregulated, leading to a decrease in immune cell recruitment.
   • Resolution of Edema:
     • Resolution mechanisms contribute to the clearance of excess fluid and proteins, reducing tissue swelling.

These processes work in concert to resolve inflammation, ensuring that the immune response is appropriately regulated and that tissue function is restored. The return to tissue homeostasis is a finely orchestrated process involving a balance between pro-inflammatory and anti-inflammatory signals, immune cell activation and clearance, and tissue repair mechanisms. Dysregulation of the resolution phase can contribute to chronic inflammatory conditions and tissue damage.

Next Topic: Endotoxin Tolerance to LPS and Other TLR-Recognized PAMPs

Source: ChatGPT response prompted and edited by Joel Graff.

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