cells Review Microbiota-Dependent Effects of IL-22 Morsal Sabihi , Marius Böttcher, Penelope Pelczar and Samuel Huber * I. Department of Medicine, University Medical Center Hamburg-Eppendorf, Martinistr. 52, 20246 Hamburg, Germany; [email protected] (M.S.); [email protected] (M.B.); [email protected] (P.P.) * Correspondence: [email protected]; Tel.: +49-40-7410-53910 Received: 31 August 2020; Accepted: 25 September 2020; Published: 29 September 2020 Abstract: Cytokines are important contributors to immune responses against microbial and environmental threats and are of particular importance at epithelial barriers. These interfaces are continuously exposed to external factors and thus require immune components to both protect the host from pathogen invasion and to regulate overt inflammation. Recently, substantial efforts have been devoted to understanding how cytokines act on certain cells at barrier sites, and why the dysregulation of immune responses may lead to pathogenesis. In particular, the cytokine IL-22 is involved in preserving an intact epithelium, maintaining a balanced microbiota and a functioning defense system against external threats. However, a tight regulation of IL-22 is generally needed, since uncontrolled IL-22 production can lead to the progression of autoimmunity and cancer. Our aim in this review is to summarize novel findings on IL-22 and its interactions with specific microbial stimuli, and subsequently, to understand their contributions to the function of IL-22 and the clinical outcome. We particularly focus on understanding the detrimental effects of dysregulated control of IL-22 in certain disease contexts. Keywords: IL-22; IL-22BP; IL-22R1; microbiota; cytokines; inflammation 1. Introduction A highly diverse microbiome contributes to the development and maturation of a robust immune system, and is an important factor in maintaining homeostasis at barrier sites [1]. Many beneficial physiological functions arise due to the mutualistic relationship between the host and its microbiome. The host provides a nutrient rich space, whereas resident microbes catabolize and facilitate the acquisition of food molecules. Moreover, components derived from the commensal microbiota prevent the colonization and propagation of pathogenic microbes at these interfaces [2]. Considerably, constant food and microbial antigen exposures at epithelial barriers modulating immune components, have a critical role in the development of the host and progression of immune-related diseases [3]. The host microbiota is closely associated to the regulation of cytokine expression patterns. The composition of the microbiota can be altered easily through changes to the diet, antibiotic intake or substance abuse, and can even undergo diurnal oscillation [3–6]. Specific factors attributed to the microbiota and related by-products have been discovered to induce dysregulated cytokine expression and inflammation that may be left uncontrolled after a threat has subsided. Under such circumstances, these factors may contribute to the development of chronic inflammation, autoimmunity and cancer by enhancing expression of certain cytokines [7]. Interleukin-22 (IL-22) is one such cytokine that has many protective qualities, but requires constant regulation to prevent overproduction in inflammatory settings [8]. IL-22 is involved in many aspects of the immune system, in that it is an active modulator in preserving an intact epithelium [9–12], maintaining a balanced microbiota [13] and a functioning defense system against external threats [13]. IL-22 belongs to the IL-10 family, a family of cytokines Cells 2020, 9, 2205; doi:10.3390/cells9102205 www.mdpi.com/journal/cells CellsCells 20202020,, 99,, 2205x FOR PEER REVIEW 22 ofof 1920 that is grouped based on their structural similarity, common receptor usage, and similar downstream thatsignaling is grouped targets based [14]. on The their description structural of similarity, IL-22 was common contemporaneously receptor usage, reported and similar by Renauld downstream and signalingGurney, and targets was [first14]. referred The description to as the ofIL-10-relat IL-22 wased contemporaneouslyT cell-derived inducible reported factor by (IL-TIF) Renauld [15,16]. and Gurney,IL-22 is an and α-helical was first cytokine, referred comprising to as the IL-10-related of six α-helices T cell-derived and connecting inducible loops. factor This (IL-TIF) cytokine [15 binds,16]. α α IL-22to a heterodimeric is an -helical cell cytokine, surface comprising receptor complex of six -helicescomprising and connectingof the IL-10R2 loops. and This IL-22R1 cytokine subunits. binds IL- to a22R1 heterodimeric defines the cell specificity surface receptor of IL-22, complex as it comprisingis predominantly of the IL-10R2 expressed and IL-22R1on epithelial subunits. cells IL-22R1 of the definesgastrointestinal the specificity tract, ofurogenital IL-22, as ittract, is predominantly lung and skin, expressed but is absent on epithelial on hematopoietic cells of the cells gastrointestinal within these tract,tissues urogenital [17]. tract, lung and skin, but is absent on hematopoietic cells within these tissues [17]. ThroughThrough thethe membranemembrane boundbound IL-22R1,IL-22R1, IL-22 is ableable toto signalsignal fromfrom thethe immuneimmune systemsystem toto thethe tissue.tissue. IL-22IL-22 is is predominantly predominantly produced produced by Tby helper T he 17lper (Th17), 17 (Th17), T helper T 22helper (Th22), 22 and (Th22), innate and lymphoid innate γδ cellslymphoid type 3cells (ILC3) type [18 3– (ILC3)23]. Other [18–23]. cellular Other sources cellular of sources IL-22 include of IL-22 includeT cells, neutrophilsγδ T cells, neutrophils and NK T cellsand NK [17]. T Activationcells [17]. Activation of the IL-22R1 of the leads IL-22R1 to an leads activation to an activation of Janus kinaseof Janus 1 (Jak1)kinase and 1 (Jak1) non-receptor and non- proteinreceptor tyrosine protein kinase tyrosine 2 (Tyk2) kinase [24 ].2 This(Tyk2) activation [24]. leadsThis toactivation tyrosine residueleads to phosphorylation tyrosine residue of STAT3.phosphorylation In addition of toSTAT3. STAT3, In STAT1 addition and to STAT5 STAT3, have STAT1 also beenand STAT5 reported have to be also activated been reported by IL-22 to [24 be]. Distinctactivated additional by IL-22 pathways[24]. Distinct have additional been described pathwa to beys involvedhave been in IL-22described signaling, to be includinginvolved Mitogenin IL-22 Activationsignaling, including Protein Kinase Mitogen (MAPK), Activation Akt [ 25Protein] and p38Kinase pathways (MAPK), [26 Akt]. [25] and p38 pathways [26]. IL-22IL-22 isis knownknown toto playplay aa rolerole inin multiplemultiple diseasesdiseases suchsuch asas inflammatoryinflammatory bowelbowel diseasedisease (IBD),(IBD), psoriasis,psoriasis, arthritis and and cancer cancer [8,17]. [8,17 ].In general, In general, IL-2 IL-222 is considered is considered to have to pr haveotective protective effects eatff ectsbarrier at barriersites exposed sites exposed to external to external stimuli stimuli in an inacute an acute setting, setting, however, however, chronic chronic inflammation inflammation can can result result in indysregulation dysregulation of ofIL-22 IL-22 signaling, signaling, promoting promoting overt overt tissue tissue damage damage and and cancer cancer [27]. [27 Interestingly,]. Interestingly, the theimpact impact of IL-22 of IL-22 in these in these diseases diseases can canbe variable, be variable, which which may may be attributed be attributed to the to microbial the microbial factors factors that thataffect aff theect theactions actions of this of this cytokine. cytokine. In Inorder order to toda dampenmpen possible possible pathogenic pathogenic effects, effects, it it is crucial toto modulatemodulate IL-22IL-22 byby eithereither controllingcontrolling thethe productionproduction ofof IL-22IL-22 oror byby blockingblocking itit directlydirectly viavia itsits solublesoluble endogenousendogenous receptor,receptor, thethe IL-22IL-22 bindingbinding proteinprotein (IL-22BP)(IL-22BP) (Figure (Figure1 )[1)27 [27,28].,28]. FigureFigure 1.1. IL-22IL-22 regulationregulation atat mucosalmucosal barriers.barriers. IL-22 is aa criticalcritical cytokinecytokine thatthat isis highlyhighly producedproduced atat epithelialepithelial barriers.barriers. IL-22 is one of many factors that isis responsibleresponsible forfor fortificationfortification ofof thethe epithelialepithelial layerlayer toto preventprevent thethe translocationtranslocation ofof pathogenspathogens andand toto promotepromote woundwound repair.repair. IL-22IL-22 isis predominantlypredominantly producedproduced byby CD4 CD4++ T cellsT cells and and ILC3 ILC3 populations, populations, among among others. others. Signaling Signaling via the heterodimervia the heterodimer receptor comprisingreceptor comprising of IL-10R2 of and IL-10R2 IL-22R1 and initiates IL-22R1 JAK initiate ands Tyk JAK kinases and Tyk to activatekinases STATto activate proteins, STAT which proteins, then translocatewhich then to translocate the nucleus to andthe nucleu induces expression and induce of expression antimicrobial of antimicrobial peptide, mucin, peptide, and cell mucin, proliferation and cell genes.proliferation IL-22BP genes. is the IL-22BP soluble is endogenous the soluble endogenous receptor ofIL-22, receptor whose of IL-22, purpose whose is topurpose inhibit is binding to inhibit of IL-22binding to membraneof IL-22 to boundmembrane IL-22R1. bound Created IL-22R1. with Created BioRender.com