Peripheral Administration of IL-13 Induces Anti-inflammatory Microglial/Macrophage Responses and Provides Neuroprotection in Ischemic Stroke

Abstract

Neuroinflammation is strongly induced by cerebral ischemia. The early phase after the onset of ischemic stroke is characterized by acute neuronal injury, microglial activation, and subsequent infiltration of blood-derived inflammatory cells, including macrophages. Therefore, modulation of the microglial/macrophage responses has increasingly gained interest as a potential therapeutic approach for the ischemic stroke. In our study, we investigated the effects of peripherally administered interleukin 13 (IL-13) in a mouse model of permanent middle cerebral artery occlusion (pMCAo). Systemic administration of IL-13 immediately after the ischemic insult significantly reduced the lesion volume, alleviated the infiltration of CD45 + leukocytes, and promoted the microglia/macrophage alternative activation within the ischemic region, as determined by arginase 1 (Arg1) immunoreactivity at 3 days post-ischemia (dpi). Moreover, IL-13 enhanced the expression of M2a alternative activation markers Arg1 and Ym1 in the peri-ischemic (PI) area, as well as increased plasma IL-6 and IL-10 levels at 3 dpi. Furthermore, IL-13 treatment ameliorated gait disturbances at day 7 and 14 and sensorimotor deficits at day 14 post-ischemia, as analyzed by the CatWalk gait analysis system and adhesive removal test, respectively. Finally, IL-13 treatment decreased neuronal cell death in a coculture model of neuroinflammation with RAW 264.7 macrophages. Taken together, delivery of IL-13 enhances microglial/macrophage antiinflammatory responses in vivo and in vitro, decreases ischemia-induced brain cell death, and improves sensory and motor functions in the pMCAo mouse model of cerebral ischemia.

Murine induced pluripotent stem cell‐derived neuroimmune cell culture models emphasize opposite immune‐effector functions of interleukin 13‐primed microglia and macrophages in terms of neuroimmune toxicity

“…Our preceding studies have shown that local administration of IL13 at the onset of neuroinflammation promotes alternative activation of lesion-associated myeloid cells in mouse models of spinal cord injury (SCI) (Dooley et al, 2016), cuprizone (CPZ)-induced CNS inflammation and demyelination (Guglielmetti et al, 2016;Le Blon et al, 2016), temporal lobe epilepsy (Ali et al, 2017), and middle cerebral artery occlusion (MCAO)-induced stroke (Hamzei Taj et al, 2018). Furthermore, we and/or others have shown that IL13 treatment is associated with improved histopathological and/or functional recovery in SCI, CPZ, and MCAO models (Dooley et al, 2016;Guglielmetti et al, 2016;Kolosowska et al, 2019;Le Blon et al, 2016), suggesting a rationale for the use of IL13 as a future supportive therapeutic agent in CNS trauma (Quarta, Berneman, & Ponsaerts, 2020).…”

Implications of Sex Differences in Immunity for SARS-CoV-2 Pathogenesis and Design of Therapeutic Interventions

“…Treatment strategies are available to antagonize androgen-mediated effects, which can promote protective ILC2 and Th22 cell responses when initiated early during SARS-CoV-2 infection. Recombinant amphiregulin has shown beneficial effects in influenza-infected mice, and IL-13 has been proposed as a therapeutic intervention to reduce inflammation and promote tissue repair in preclinical models of stroke ( Kolosowska et al., 2019 ). However, given the pro-inflammatory role of cytokines in immune-mediated diseases such as Crohn’s disease and rheumatoid arthritis, as well as enhanced levels detected in COVID-19 patients ( Lucas et al., 2020 ; Mateen et al., 2019 ; Shah et al., 2018 ), the timing of initiation of immune-therapies in SARS-CoV-2 infection will be critical to promote viral containment and tissue resilience without contributing to the cytokine release syndrome in the advanced stages of COVID-19.…”

Type 2 Innate Lymphoid Cells Accumulate in the Brain After Hypoxia-Ischemia but Do Not Contribute to the Development of Preterm Brain Injury

“…The immune response in neonates is biased toward the Th2 type (Adkins et al, 2004;Debock and Flamand, 2014), but after HI insult there is a Th1/Th17-type immune response in the neonatal mouse brain (Albertsson et al, 2014;Yang et al, 2014) and blockage of lymphocyte trafficking to the brain is neuroprotective (Yang et al, 2014). Further, the Th2 cytokines IL-4 and IL-13 have been found to protect the mouse brain from injury (Walsh et al, 2015;Kolosowska et al, 2019).…”