IL-38 Gene Deletion Worsens Murine Colitis

Area of Science:

• Immunology
• Gastroenterology
• Cytokine Biology

Background:

• Interleukin-38 (IL-38) is a recently identified cytokine within the IL-1 Family, primarily produced by B lymphocytes.
• IL-38 possesses anti-inflammatory properties and plays a role in maintaining intestinal homeostasis.
• Human studies suggest IL-38 may be protective against inflammatory bowel diseases (IBD) like ulcerative colitis and Crohn's disease.

Purpose of the Study:

• To investigate the role of endogenous IL-38 in experimental colitis.
• To determine the impact of IL-38 deficiency on colitis severity and associated inflammatory pathways in mice.

Main Methods:

• Generation of IL-38 deficient mice by deleting exons 1-4.
• Induction of experimental colitis using dextran sulfate sodium (DSS) in wild-type (WT) and IL-38 deficient mice.
• Assessment of disease severity, intestinal permeability, histological damage, and inflammatory markers including NLRP3 inflammasome components, caspase-1, IL-1β, IL-1α, myeloperoxidase, and IL-17A/F.
• Treatment of IL-38 deficient mice with an NLRP3 inhibitor.

Main Results:

• IL-38 deficient mice exhibited exacerbated DSS-induced colitis, characterized by increased weight loss, intestinal permeability, and colonic neutrophil influx.
• Absence of IL-38 led to elevated colonic NLRP3 mRNA and protein, increased caspase-1 activation, and heightened processing of IL-1β.
• Expression of IL-1α, myeloperoxidase, IL-17a, and Il17f were upregulated in IL-38 deficient mice.
• NLRP3 inhibition attenuated disease severity during the recovery phase in IL-38 deficient mice.

Conclusions:

• Endogenous IL-38 functions as an anti-inflammatory cytokine that ameliorates DSS-induced colitis.
• A relative deficiency in IL-38 may contribute to IBD pathogenesis by allowing NLRP3 inflammasome overactivation.
• Targeting IL-38 or the NLRP3 inflammasome could represent potential therapeutic strategies for IBD.