IL-1α protects intestinal barrier in murine visceral leishmaniasis

Abstract

ABSTRACT Interleukin-1 (IL-1) is a pleiotropic cytokine important in inflammatory and infectious diseases, but its roles in visceral leishmaniasis (VL) remain poorly understood. Here, we evaluated the role of IL-1 cytokines during experimental visceral leishmaniasis. We showed that IL-1 receptor 1 (IL-1R1) deficiency enhanced the gamma interferon (IFNγ)-mediated response and restricted parasites in an IL-1α-dependent manner, whereas IL-1β deficiency had no effect. The absence of IL-1R1 and IL-1α led to intestinal microbiota dysbiosis. The infection induced IL-1α expression in the gut. The absence of IL-1α led to reduced expression of tight-junction molecules, increased intestinal permeability, and bacterial translocation. These alterations amplified non-Leishmania-specific IFN-γ production, which was reversed by broad-spectrum antibiotic treatment. Bone marrow chimeric transplantation showed that hematopoietic cells are the source of IL-1α during VL. Together, our findings reveal that IL-1α acts as a key regulator of gut barrier integrity in VL and indirectly restrains systemic IFNγ-driven inflammation. This work highlights IL-1α-dependent intestinal protection as an overlooked component of VL pathogenesis. IMPORTANCE Visceral leishmaniasis (VL) is a systemic and chronic disease caused by Leishmania parasites. Most infected individuals remain asymptomatic due to an appropriate IFNγ-mediated response. By contrast, the disease progression is characterized by excessive inflammation, with high levels of cytokines, among them IFNγ. IL-1 cytokines play a role in modulating immune responses and epithelial barriers. We report that IL-1α protects the intestinal environment and indirectly regulates the IFNγ-mediated response during experimental VL. The infection induces IL-1α expression in the intestine, and its absence leads to dysbiosis, gut permeability, and bacterial translocation. Overall, this study reveals the role of IL-1α in intestinal integrity during VL and in regulating the IFNγ-mediated response. Expanding the knowledge of IL-1α in intestinal protection may support therapeutic approaches to improve the outcomes of infection. Visceral leishmaniasis (VL) is a systemic and chronic disease caused by Leishmania parasites. Most infected individuals remain asymptomatic due to an appropriate IFNγ-mediated response. By contrast, the disease progression is characterized by excessive inflammation, with high levels of cytokines, among them IFNγ. IL-1 cytokines play a role in modulating immune responses and epithelial barriers. We report that IL-1α protects the intestinal environment and indirectly regulates the IFNγ-mediated response during experimental VL. The infection induces IL-1α expression in the intestine, and its absence leads to dysbiosis, gut permeability, and bacterial translocation. Overall, this study reveals the role of IL-1α in intestinal integrity during VL and in regulating the IFNγ-mediated response. Expanding the knowledge of IL-1α in intestinal protection may support therapeutic approaches to improve the outcomes of infection.