Expanding Role of Interleukin-1 Family Cytokines in Acute Ischemic Stroke

Abstract

Ischemic stroke (IS) is a critical medical condition that results in significant neurological deficits and tissue damage, affecting millions worldwide. Currently, there is a significant lack of reliable tools for assessing and predicting IS outcomes. The inflammatory response following IS may exacerbate tissue injury or provide neuroprotection. This review sought to summarize current knowledge on the IL-1 family's involvement in IS, which includes pro-inflammatory molecules, such as IL-1α, IL-1β, IL-18, and IL-36, as well as anti-inflammatory molecules, like IL-1Ra, IL-33, IL-36A, IL-37, and IL-38. The balance between these opposing inflammatory processes may serve as a biomarker for determining patient outcomes and recovery paths. Treatments targeting these cytokines or their receptors show promise, but more comprehensive research is essential to clarify their precise roles in IS development and progression.

Keywords: cytokines; immunology; inflammation; interleukin; stroke.

Figure 1

The cascade following an ischemic stroke. Figure abbreviations: BBB—blood brain barrier, DAMPs—damage-associated molecular patterns, MMPs—matrix metalloproteinases.

Figure 2

Anti-inflammatory (green half) and pro-inflammatory (red half) IL-1 family cytokines in ischemic stroke. Figure abbreviations: IL-1α—interleukin-1α, IL-1β—interleukin-1β, IL-1Ra—interleukin-1 receptor antagonist, IL-18—interleukin-18, IL-33—interleukin-33, IL-36—interleukin-36, IL-36Ra—interleukin-36 receptor antagonist, IL-37—interleukin-37, IL-38—interleukin-38.

Figure 3

The IL-1 signaling pathway and its regulatory mechanisms. Figure abbreviations: AP-1—activator protein 1; IL-1α—interleukin-1α; IL-1β—interleukin-1β; IL-1R1—interleukin-1 receptor type 1; IL-1Ra—interleukin 1 receptor antagonist; IL-1RAcP—interleukin-1 receptor accessory protein; IL-1R2—interleukin-1 receptor type 2; IL-38—interleukin-38; IRAK—interleukin-1 receptor-associated kinases; MAPK—mitogen-activated protein kinases; Myd88—myeloid differentiation primary response protein 88; NF-κB—nuclear factor-kappa B; TIR domain—the toll-interleukin-1 receptor homology domain; TRAF6—tumor necrosis factor receptor associated factor 6.

Figure 4

IL-18 activity modulated by IL-12 and IL-15 interplay. Figure abbreviations: CD—cluster of differentiation; FasL—Fas ligand; IFN-γ—interferon-gamma; IL—interleukin; NK—natural killer; Th—T helper; ↑—increased.

Figure 5

IL-33 role in ischemic stroke. Figure abbreviations: AREG—amphiregulin; EGFR—epidermal growth factor receptors; IL—interleukin; ILC2s—group 2 innate lymphoid cells; TGF-β—transforming growth factor β; Th—lymphocyte T helper; Treg—regulatory T cells; ↓—decreased; ↑—increased.

Figure 6

IL-37 and IL-18: shared receptors, opposing functions. Figure abbreviations: IL-18—interleukin-18; IL-18BP—IL-18 binding protein; IL-18Rα—IL-18 receptor alpha chain; IL-18Rβ—IL-18 receptor beta chain; IL-1R8—IL-1 receptor 8; IL-37—interleukin-37.