Susana M Fernandes1, Ana R Pires2, Cristina Ferreira3, Russell B Foxall2, José Rino2, Carla Santos4, Luís Correia5, José Poças6, Henrique Veiga-Fernandes2, Ana E Sousa2. 1. Instituto de Medicina Molecular, Faculdade de Medicina, Universidade de Lisboa Clínica Universitária de Medicina II. 2. Instituto de Medicina Molecular, Faculdade de Medicina, Universidade de Lisboa. 3. Serviço de Anatomia Patológica. 4. Clínica Universitária de Doenças Infecciosas. 5. Clínica Universitária de Gastroenterologia, Hospital de Santa Maria, Centro Hospitalar Lisboa Norte-EPE, Lisboa. 6. Serviço de Infecciologia, Hospital de S. Bernardo, Setúbal, Portugal.
Abstract
BACKGROUND: Interleukin 22 (IL-22) is emerging as a key cytokine for gut epithelial homeostasis and mucosal repair. Gut disruption is a hallmark of human immunodeficiency virus (HIV) infection. Here, we investigated IL-22 production and gut mucosal integrity in HIV type 1 (HIV-1)-infected individuals receiving long-term antiretroviral therapy (ART). METHODS: Biopsy specimens from 37 individuals who underwent colonoscopy primarily for cancer screening and from 17 HIV-1-infected and 20 healthy age-matched controls were assessed. RESULTS: We found significant depletion of sigmoid IL-22-producing CD4(+) T cells (T-helper type 22 [Th22] cells) even after prolonged ART, contrasting with the apparently normal compartments of regulatory and interleukin 17 (IL-17)-producing CD4(+) T cells, as well as total mucosal CD4(+) T cells. Despite the preferential Th22 cell depletion, IL-22 production by innate lymphoid cells (ILCs) was similar to that observed in HIV-1-seronegative subjects, and transcription of genes encoding molecules relevant for IL-22 production (ie, AHR, IL23, IL23R, IL1B, IL6, and TGFB1) was preserved. Remarkably, levels of transcripts of IL-22-target genes (ie, REG3G, DEFB4A, S100A9, MUC1, and MUC13) were unaltered, suggesting an adequate production of antimicrobial peptides and mucins. In agreement, enteric epithelial architecture was fully preserved. CONCLUSIONS: Despite the reduced Th22 cell subset, innate IL-22-mediated mechanisms, essential for sigmoid mucosa integrity, were fully operational in long-term-treated HIV-1-infected individuals. Our data highlight IL-22 production by ILCs as an important target for therapies aimed at facilitating human mucosal reconstitution.
BACKGROUND:Interleukin 22 (IL-22) is emerging as a key cytokine for gut epithelial homeostasis and mucosal repair. Gut disruption is a hallmark of human immunodeficiency virus (HIV) infection. Here, we investigated IL-22 production and gut mucosal integrity in HIV type 1 (HIV-1)-infected individuals receiving long-term antiretroviral therapy (ART). METHODS: Biopsy specimens from 37 individuals who underwent colonoscopy primarily for cancer screening and from 17 HIV-1-infected and 20 healthy age-matched controls were assessed. RESULTS: We found significant depletion of sigmoid IL-22-producing CD4(+) T cells (T-helper type 22 [Th22] cells) even after prolonged ART, contrasting with the apparently normal compartments of regulatory and interleukin 17 (IL-17)-producing CD4(+) T cells, as well as total mucosal CD4(+) T cells. Despite the preferential Th22 cell depletion, IL-22 production by innate lymphoid cells (ILCs) was similar to that observed in HIV-1-seronegative subjects, and transcription of genes encoding molecules relevant for IL-22 production (ie, AHR, IL23, IL23R, IL1B, IL6, and TGFB1) was preserved. Remarkably, levels of transcripts of IL-22-target genes (ie, REG3G, DEFB4A, S100A9, MUC1, and MUC13) were unaltered, suggesting an adequate production of antimicrobial peptides and mucins. In agreement, enteric epithelial architecture was fully preserved. CONCLUSIONS: Despite the reduced Th22 cell subset, innate IL-22-mediated mechanisms, essential for sigmoid mucosa integrity, were fully operational in long-term-treated HIV-1-infected individuals. Our data highlight IL-22 production by ILCs as an important target for therapies aimed at facilitating human mucosal reconstitution.
Authors: Stephanie M Dillon; Moriah J Castleman; Daniel N Frank; Gregory L Austin; Sara Gianella; Andrew C Cogswell; Alan L Landay; Edward Barker; Cara C Wilson Journal: J Acquir Immune Defic Syndr Date: 2017-12-01 Impact factor: 3.731
Authors: S M Fernandes; A R Pires; P Matoso; C Ferreira; H Nunes-Cabaço; L Correia; E Valadas; J Poças; P Pacheco; H Veiga-Fernandes; R B Foxall; A E Sousa Journal: Mucosal Immunol Date: 2017-05-17 Impact factor: 7.313
Authors: Amanda B Macedo; Camille L Novis; Caroline M De Assis; Eric S Sorensen; Paula Moszczynski; Szu-Han Huang; Yanqin Ren; Adam M Spivak; R Brad Jones; Vicente Planelles; Alberto Bosque Journal: JCI Insight Date: 2018-10-04