A Role for Leukocyte-Derived IL-1RA in DC Homeostasis Revealed by Increased Susceptibility of IL-1RA-Deficient Mice to Cutaneous Leishmaniasis

Abstract

Dendritic cell (DC)-derived IL-1α/β plays a critical role in the induction of T helper type 1 (Th1)-dependent immunity against Leishmania. DCs from susceptible BALB/c mice produce less IL-1α/β when compared with resistant C57BL/6 mice, contributing to aberrant Th2 development and ultimate death of infected mice. We have extended our studies of the role of IL-1 in leishmaniasis using IL-1RA(-/-) BALB/c mice that are characterized by upregulated IL-1 receptor signaling. Unexpectedly, infection of IL-1RA(-/-) mice led to significantly worsened disease outcome with larger lesions, dramatically higher parasite burdens, and decreased IFN-γ production by antigen-specific T cells. We determined that IL-1RA(-/-) DCs were more mature already in the steady state, exhibited less phagocytotic capacity, and IL-12 production in response to various stimuli was impaired. Our data suggest that in addition to effects on Th education, IL-1α/β signaling also modulates DC homeostasis with increased signaling, leading to downmodulation of IL-12 synthesis and worsened disease outcome after infection with Leishmania major. Thus, the complex regulation of various members of the IL-1 cytokine family mediated through effects on both DCs and T cells critically contributes to disease outcome against this important human pathogen.

Immune responses against protozoan parasites: a focus on the emerging role of Nod-like receptors

“…Consistent with this finding, a local IL-1β injection accelerates the progression of lesions in L. amazonensis– infected C57BL/6 mice [89]. Furthermore, IL-1 receptor antagonist–deficient ( Il1ra −/− ) BALB/c mice, which have heightened IL-1α and IL-1β signaling, are highly susceptible to leishmaniasis [88,90]. The resistance in Il1a −/− and Il1b −/− mice is correlated with a subsequent increase in IFN-γ and a decrease in IL-4–producing T cells [88,90].…”

“…Furthermore, IL-1 receptor antagonist–deficient ( Il1ra −/− ) BALB/c mice, which have heightened IL-1α and IL-1β signaling, are highly susceptible to leishmaniasis [88,90]. The resistance in Il1a −/− and Il1b −/− mice is correlated with a subsequent increase in IFN-γ and a decrease in IL-4–producing T cells [88,90]. Similar results were observed in T cells from susceptible Il1ra −/− mice during L. major infections.…”

Immunopathogenesis of non-healing American cutaneous leishmaniasis and progressive visceral leishmaniasis

“…Their protective roles are likely to be in conjunction with Th1 cell activation. Their detrimental roles are mediated via the regulation of additional waves of neutrophil recruitment, promoting lesion progression and tissue damage, as elegantly illustrated in L. major -susceptible mice [159, 160] and suggested in the above-mentioned human infections with L. braziliensis . Secondly, host factors that trigger MΦ alternative activation (IL-4, IL-10, IL-13, and TGF-β insulin-like growth factor) or MΦ suboptimal activation (low levels of IFN-γ and TNF-α) can create a microenvironment in favor of amastigote replication [46, 63].…”

IL-1RA regulates immunopathogenesis during fungal-associated allergic airway inflammation

“…Moreover, IL-1RA-mediated regulation of IFN-γ has been shown in models of Toxoplasma gondii-mediated arthritis (51) and experimental autoimmune encephalomyelitis (52). IL-1RA is required for the induction of IFN-γ during cutaneous Leishmania major infection (53). Other studies have shown that treatment of human PBMCs with IL-1RA had no effect on Staphylococcus epidermidis-induced IFN-γ production (54).…”