Resolution of inflammation: an integrated view

Abstract

Resolution of inflammation is a coordinated and active process aimed at restoration of tissue integrity and function. This review integrates the key molecular and cellular mechanisms of resolution. We describe how abrogation of chemokine signalling blocks continued neutrophil tissue infiltration and how apoptotic neutrophils attract monocytes and macrophages to induce their clearance. Uptake of apoptotic neutrophils by macrophages reprograms macrophages towards a resolving phenotype, a key event to restore tissue homeostasis. Finally, we highlight the therapeutic potential that derives from understanding the mechanisms of resolution.

Figure 1

Cellular interplay during resolution of inflammation. Overview of cellular processes during onset (left) and resolution (right) of inflammation. During early phases of inflammation tissue-resident cells sense damage and launch the release of signals that induce rapid neutrophil and delayed monocyte emigration. Resolution is initiated when neutrophils become apoptotic thus secreting mediators that inhibit continued neutrophil infiltration. Ingestion of apoptotic neutrophils changes the macrophage phenotype towards a resolution-phase macrophage, which promotes return to tissue homeostasis. A switch in tissue (stromal) cells can also contribute to generate the initial signals for resolution to start.

Figure 2

Mechanisms of neutrophil- and macrophage-driven resolution. A. Depletion of chemokines during resolution. MMPs cleave CC and CXC chemokines rendering them non-functional. Structural decoy receptors such as D6 and DARC sequester chemokines without subsequent signal transduction. Functional decoy receptors are classical chemokine receptors with repressed signalling. B. Factors controlling neutrophil life span at sites of inflammation. Interestingly, the pro-apoptotic stimuli can often override those that augment neutrophil life span. C. Upon apoptosis find me signals such as nucleotides, S1P, CX₃CL1 and LPC are released that attract scavengers. These recognize apoptotic cells via eat me signals exposed on the cell surface. Clearance is mediated by direct cell–cell contact or by involvement of bridging molecules. D. In response to local mediators and upon efferocytosis, pro-inflammatory macrophages switch to resolution-phase macrophages.

Figure 3

Role of accessory cells in resolution. MDSCs clear apoptotic neutrophils, release anti-inflammatory IL10 and contribute to the expansion of T_Reg. T_Reg stimulate neutrophil apoptosis, enhance the efferocytosis capacity of macrophages and secrete resolving cytokines like IL10 and TGF-β in a contact-dependent manner.