IL-22 Mediates Goblet Cell Hyperplasia and Worm Expulsion in Intestinal Helminth Infection

Abstract

Type 2 immune responses are essential in protection against intestinal helminth infections. In this study we show that IL-22, a cytokine important in defence against bacterial infections in the intestinal tract, is also a critical mediator of anti-helminth immunity. After infection with Nippostrongylus brasiliensis, a rodent hookworm, IL-22-deficient mice showed impaired worm expulsion despite normal levels of type 2 cytokine production. The impaired worm expulsion correlated with reduced goblet cell hyperplasia and reduced expression of goblet cell markers. We further confirmed our findings in a second nematode model, the murine whipworm Trichuris muris. T.muris infected IL-22-deficient mice had a similar phenotype to that seen in N.brasiliensis infection, with impaired worm expulsion and reduced goblet cell hyperplasia. Ex vivo and in vitro analysis demonstrated that IL-22 is able to directly induce the expression of several goblet cell markers, including mucins. Taken together, our findings reveal that IL-22 plays an important role in goblet cell activation, and thus, a key role in anti-helminth immunity.

Neutrophil Elastase and Interleukin 17 Expressed in the Pig Colon during Brachyspira hyodysenteriae Infection Synergistically with the Pathogen Induce Increased Mucus Transport Speed and Production via Mitogen-Activated Protein Kinase 3

“…In airway epithelial cells, several inflammatory cytokines (IL-1␤, IL-4, IL-6, IL-9, IL-13, IL-17A, and TNF-␣) have been described to be involved in MUC5AC expression in vitro (14). In nematode infections, MUC5AC induction is predominantly regulated by IL-13 (5), while IL-22 participates in goblet cell activation (36). IL-1␤ has been suggested to be involved in MUC5AC induction in a colonic cell line by Shigella dysenteriae (37), and IL-17A is thought to induce MUC5AC through the NF-B signaling pathway in human bronchial cells in vitro (15).…”

Functional and phenotypic heterogeneity of group 3 innate lymphoid cells

“…These antimicrobial peptides act to regulate spatial segregation of commensal bacteria from the epithelial barrier by establishing a gradient of bactericidal activity, which has been termed the ‘demilitarized zone’ 77. Production of IL‐22 further reinforces spatial segregation of commensal bacteria by driving transcription of membrane‐bound mucins and goblet cell hyperplasia 78, 79…”

“…Nonetheless, NKp46 + ILC3 may have other important non‐redundant roles during C. rodentium infection, as infected mice lacking NKp46 + ILC3 exhibited severe caecal damage 84. In addition, intestinal ILC3‐derived IL‐22 may also contribute to immunity roles in a diverse range of clinically relevant infections in the gut including the nosocomial pathogen Clostridium difficile ,119 rotavirus,120 the fungal pathogen Candida albicans ,121 as well as gastrointestinal helminths 78. In contrast, some enteric pathogens have evolved to circumvent and exploit the ILC3 response to infection.…”

Immunity to gastrointestinal nematode infections

“…171 Consistent with these data, Muc5ac is only upregulated in resistant mouse strains 170 and Muc5ac-deficient mice have impaired expulsion of T. muris, N. brasiliensis, and T. spiralis. 173 Increased mucus production and the mucin switch are largely driven by IL-13, 173 IL-4, 174 and IL-22, 175 but the principle of physical obstruction provided by mucus layers can also be extended to other mucosal sites such as the lungs where the lectin surfactant protein-D, which acts as a lubricant, is needed for optimal protection against the pulmonary stage of N. brasiliensis infection. 176 Another expulsion mechanism is the release of various proteins by activated granulocytes and epithelial cells, most of which are toxic to parasites.…”