The role of IL-22 in the resolution of sterile and nonsterile inflammation

Abstract

In a broad sense, inflammation can be conveniently characterised by two phases: the first phase, which is a pro-inflammatory, has evolved to clear infection and/or injured tissue; and the second phase concerns regeneration of normal tissue and restitution of normal physiology. Innate immune cell-derived pro-inflammatory cytokines and chemokines activate and recruit nonresident immune cells to the site of infection, thereby amplifying the inflammatory responses to clear infection or injury. This phase is followed by a cytokine milieu that promotes tissue regeneration. There is no absolute temporal distinction between these two phases, and cytokines may have dual pleiotropic effects depending on the timing of release, inflammatory microenvironment or concentrations. IL-22 is a cytokine with reported pro- and anti-inflammatory roles; in this review, we contend that this protein has primarily a function in restitution of normal tissue and physiology.

Keywords: T helper 17 cells; hepatitis; inflammatory bowel disease; inflammatory diseases; innate lymphoid cells; interleukins.

Figure 1

A diagram illustrating a summary of the pathways and roles of interleukin‐22 (IL‐22) following sterile and nonsterile injury. (1) The presence of sterile injury, for example by drugs, or nonsterile injury, for example by infections (2), will lead to cell injury and/or death activating damage‐associated molecular patterns (DAMP) and pathogen‐associated molecular patterns (PAMPs) that signal an immune response. (3)(a) Along with several chemokines and cytokines, endogenous IL‐22 is released from either group 3 innate lymphoid cells (ILC3) and/or Th17/Th22 hours after the induction of injury. It is also proposed that group 3 ILCs (ILC3) might secrete IL‐22 at an earlier stage when compared to TH17/TH22. (3)(B) Alternatively, in experimental‐ or clinical‐based studies, exogenous IL‐22 can be injected directly via recombinant IL‐22 (rIL‐22) or adenovirus expressing IL‐22. (4) Both endogenous and exogenous IL‐22 lead to the binding and activation of IL‐22 receptor (IL‐22R) via its two subunits, IL‐22R1 and IL‐10R2. IL‐22R is commonly found on the intestinal and respiratory epithelial cells, hepatocytes, pancreatic islets and keratinocytes. The initial binding of IL‐22 occurs with the IL‐22R1 subunit, unique to IL‐22 and unlike other cytokines from IL‐10 family, followed by the binding to IL‐10R2. (5) IL‐22 binding to IL‐22R mediates biological effects via phosphorylation of signalling pathways notably via signal transducer and activator of transcription‐3 (STAT3) and activating protein‐1 (AP1), STAT1, STAT5 and nuclear factor‐kappaB (NF‐kB). The signalling from these pathways stimulates the activation of several intracellular signalling processes such as mitogen‐activated protein kinase (MAPK) pathways including c‐Jun N‐terminal kinases (JNK), p38 and extracellular signal‐regulated kinases (Erk). (6) IL‐22 promotes anti‐inflammatory responses following injury by stimulating proliferation, regeneration and repair of injured tissue. IL‐22 thus plays an essential role in the resolution of injury and restoration of homeostasis in the immune system.