Chronic inflammation: a failure of resolution?

Abstract

Inflammation has evolved as a protective response to insult or injury, it's a primordial response that eliminates or neutralises foreign organisms or material, the resolution of inflammation encompasses the endogenous anti-inflammatory mechanisms that protect us against excessive tissue injury and promote the restoration of tissue structure and function. In fact, our well being and survival depends upon its efficiency and carefully-balanced control. In general, the innate inflammatory response initiates within minutes and, if all is well, resolves within hours. In contrast, chronic inflammation persists for weeks, months or even years. Here, we are going to discuss the key endogenous checkpoints necessary for mounting an effective yet limited inflammatory response and the crucial biochemical pathways necessary to prevent its persistence.

Figure 1

Schematic illustration of the co-ordinated activation of pro-inflammatory signalling pathways by TLR ligands and the pro-inflammatory cytokines TNFα, IL-1 and IFN. Adaptor molecules (MyD88, TRADD and TRAF) and receptor associated kinases (RIP, IRAK and JAK) couple to downstream kinase cascades (MAPK; JNK, p38; TAB/TAK, IKK) which regulate the activation of transcription factors (AP-1, NF-κB, CREB and STAT) and the expression of pro-inflammatory genes. A number of negative regulatory mechanisms (shown in red) limit the activation of specific signalling pathways; SOCS targets JAK/STAT and TLR signalling; PTEN and SHIP phosphatases block PI3K; A20 and IKKα negatively regulate the NF-κB pathway; the MAPK phosphatase MKP limits activation of JNK and p38.

Figure 2

Illustration of the cellular kinetics and sequential release of mediators during the evolution of the inflammatory response from onset to resolution. (A) Inflammation causes the immediate and sequential release of signalling factors including chemokines, cytokines, eicosanoids, etc. that bring leucocytes (PMNs, eosinophils) from the microvasculature to the site of inflammation to neutralize the injurious agent. After leucocyte trafficking, peripheral blood monocytes accumulate at the inflammatory site and differentiate locally in to larger more granular phagocytosing macrophages. This is well-understood sequence of events, the inhibition of which has provided the rationale for the development of inflammatory agents. Once the inflammatory cells have neutralized the injurious agent they must be disposed of in a controlled and effective manner. Apoptotic PMNs or eosinophils are phagocytosed by macrophages, which in turn are cleared from the site of inflammation either by dying locally or by programmed cell death or by clearing to the draining lymphatics, which in the case of the inflamed peritoneum, for instance, are the parathymic lymph nodes. (B) Given a favourable genetic predisposition, failure of acute inflammation to resolve adequately could result in a predisposition to chronic inflammation, collateral tissue injury or auto-immunity typified by the accumulation of inflammatory leucocytes fibrosis and auto-antibodies to endogenous cellular and tissue antigens. (C) Thus, for the effective resolution of acute inflammation we need to curtail further influx of inflammatory leucocytes (PMNs, eosinophils, etc.), signal monocytes/macrophages to phagocytose effete leucocytes and clear all these cells form the site of injury once the inflammatory stimulus posses no further threat. One final but very important aspect of resolution is that the pro-inflammatory phenotype of the stromal cells within the injured tissue, revert back to its prior physiological state as there is evidence that chronic inflammation may be perpetuated by stromal cells attaining a phenotype that retains pro-inflammatory leucocytes at sites of inflammation longer than is necessary inhibiting their efficient clearance. For instance, it has been suggested that the interaction of stromal cells taken from site of chronic inflammation has an enhanced ability to activate leucocytes contributing to the longevity of the response.