High-Intensity Exercise Training Protects the Brain Against Autoimmune Neuroinflammation: Regulation of Microglial Redox and Pro-inflammatory Functions

Zaychik, Yifat; Fainstein, Nina; Touloumi, Olga; Goldberg, Yehuda; Hamdi, Liel; Segal, Shir; Nabat, Hanan; Zoidou, Sofia; Grigoriadis, Nikolaos; Katz, Abram; Ben‐Hur, Tamir; Einstein, Ofira

doi:10.3389/fncel.2021.640724

Cited by 27 publications

(39 citation statements)

References 58 publications

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“…The PLP 139-151 transfer EAE model in mice was utilized as previously described. [2][3][4]17 To assess the modulatory effects of ET on systemic autoimmunity, we examined in vivo and in vitro the encephalitogenicity of lymph nodes cells (LNCs) from mice that underwent the HICT program prior to proteolipid (PLP) immunization, compared with LNCs from sedentary (SED) mice (Fig. 1A).…”

Section: Experimental Designmentioning

confidence: 99%

“…Healthy mice underwent 6-wks of HICT treadmill running, including pre-and post-training performance tests on a 5-lane treadmill designed for mice (Panlab Harvard Apparatus, USA) as previously described. 3,4,17…”

Section: Treadmill Exercise Trainingmentioning

confidence: 99%

“…3 Moreover, in addition to its superior systemic immunomodulatory effect, HICT also resulted in a direct protective effect on the CNS against autoimmune neuroinflammation. 4 HICT protected the CNS against EAE development by reducing microglial-derived reactive oxygen species (ROS) formation, neurotoxicity, and pro-inflammatory responses. Thus, our and other studies [5][6][7][8][9] highlight a favorable outcome for extensive ET.…”

Section: Introductionmentioning

confidence: 99%

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Exercise training alters autoimmune cell invasion into the brain in autoimmune encephalomyelitis

Hamdi

Nabat

Goldberg

et al. 2022

Ann Clin Transl Neurol

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Background The mechanisms by which exercise training (ET) elicits beneficial effects on the systemic immune system and the central nervous system (CNS) in autoimmune neuroinflammation are not fully understood. Objectives To investigate (1) the systemic effects of high‐intensity continuous training (HICT) on the migratory potential of autoimmune cells; (2) the direct effects of HICT on blood–brain‐barrier (BBB) properties. Methods Healthy mice were subjected to high‐intensity continuous training (HICT) by treadmill running. The proteolipid protein (PLP) transfer EAE model was utilized to examine the immunomodulatory effects of training, where PLP‐reactive lymph‐node cells (LNCs) from HICT and sedentary donor mice were analyzed in vitro and transferred to naïve recipients that developed EAE. To examine neuroprotection, encephalitogenic LNCs from donor mice were transferred into HICT or sedentary recipient mice and the BBB was analyzed. Results Transfer of PLP‐reactive LNCs obtained from HICT donor mice attenuated EAE severity and inflammation in recipient mice. HICT markedly inhibited very late antigen (VLA)‐4 and lymphocyte function‐associated antigen (LFA)‐1 expression in LNCs. Transfer of encephalitogenic LNCs into HICT recipients resulted in milder EAE and attenuated CNS inflammation. HICT reduced BBB permeability and the expression of intercellular adhesion molecule (ICAM)‐1 and vascular cell adhesion molecule (VCAM)‐1 in CNS blood vessels. Interpretation HICT attenuates EAE development by both immunomodulatory and neuroprotective effects. The reduction in destructive CNS inflammation in EAE is attributed to systemic inhibition of autoreactive cell migratory potential, as well as reduction in BBB permeability, which are associated with reduced VLA‐4/VCAM‐1 and LFA‐1/ICAM‐1 interactions.

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Section: Experimental Designmentioning

confidence: 99%

Section: Treadmill Exercise Trainingmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Exercise training alters autoimmune cell invasion into the brain in autoimmune encephalomyelitis

Hamdi

Nabat

Goldberg

et al. 2022

Ann Clin Transl Neurol

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“…Microglial activation and population in HPC are reduced following exercise (Kohman et al, 2013 ; Mee-inta et al, 2019 ). High-intensity exercise serves a general neuroprotective role by reducing microglial-associated inflammation (Zaychik et al, 2021 ), which is also associated with increases in BDNF expression and improvements in spatial working memory (Xiong et al, 2015 ). Together, these data highlight how exercise is expected to reverse some of the negative consequences of ELA on glia cell proliferation and function so as to ameliorate behavioral deficits.…”

Section: Targeted Treatment Interventions For Ela Exposure: Preclinical and Clinical Findingsmentioning

confidence: 99%

Glia-Driven Brain Circuit Refinement Is Altered by Early-Life Adversity: Behavioral Outcomes

Milbocker

Campbell

Collins

et al. 2021

Front. Behav. Neurosci.

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Early-life adversity (ELA), often clinically referred to as “adverse childhood experiences (ACE),” is the exposure to stress-inducing events in childhood that can result in poor health outcomes. ELA negatively affects neurodevelopment in children and adolescents resulting in several behavioral deficits and increasing the risk of developing a myriad of neuropsychiatric disorders later in life. The neurobiological mechanisms by which ELA alters neurodevelopment in childhood have been the focus of numerous reviews. However, a comprehensive review of the mechanisms affecting adolescent neurodevelopment (i.e., synaptic pruning and myelination) is lacking. Synaptic pruning and myelination are glia-driven processes that are imperative for brain circuit refinement during the transition from adolescence to adulthood. Failure to optimize brain circuitry between key brain structures involved in learning and memory, such as the hippocampus and prefrontal cortex, leads to the emergence of maladaptive behaviors including increased anxiety or reduced executive function. As such, we review preclinical and clinical literature to explore the immediate and lasting effects of ELA on brain circuit development and refinement. Finally, we describe a number of therapeutic interventions best-suited to support adolescent neurodevelopment in children with a history of ELA.

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“…The effect of exercise strongly depends on its modality, intensity, and timing. A recent study investigating the direct effects of highintensity continuous training (HICT) on neuroprotection in the central nervous system (CNS) suggested that HICT protected the CNS against autoimmune neuroinflammation by reducing microglial-derived neurotoxicity, and proinflammatory responses, rather than inducing their shift to M2 phenotype [56]. However, it has also been observed that excessive vigorous exercise still promoted M2 polarization of macrophages in skeletal muscle, and myogenesis increases despite the increase of TNF-α [57].…”

mentioning

confidence: 99%

High-Intensity Interval Training Improves Physical Function, Prevents Muscle Loss, and Modulates Macrophage-Mediated Inflammation in Skeletal Muscle of Cerebral Ischemic Mice

Liu

Xie

Fan

et al. 2021

Mediators of Inflammation

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Although skeletal muscle is the main effector organ largely accounting for disability after stroke, considerably less attention is paid to the secondary abnormalities of stroke-related skeletal muscle loss. It is necessary to explore the mechanism of muscle atrophy after stroke and further develop effective rehabilitation strategy. Here, we evaluated the effects of high-intensity interval (HIIT) versus moderate-intensity aerobic training (MOD) on physical function, muscle mass, and stroke-related gene expression profile of skeletal muscle. After the model of middle cerebral artery occlusion (MCAO) was successfully made, the blood lactate threshold corresponding speed ( S LT ) and maximum speed ( S max ) were measured. Different intensity training protocols ( MOD < S LT ; S LT < HIIT < S max ) were carried out for 3 weeks beginning at 7 days after MCAO in the MOD and HIIT groups, respectively. We found that both HIIT and MOD prevented stroke-related gastrocnemius muscle mass loss in MCAO mice. HIIT was more beneficial than MOD for improvements in muscle strength, motor coordination, walking competency, and cardiorespiratory fitness. Furthermore, HIIT was superior to MOD in terms of reducing lipid accumulation, levels of IL-1β and IL-6 in paretic gastrocnemius, and improving peripheral blood CD4+/CD8+ T cell ratio, level of IL-10. Additionally, RNA-seq analysis revealed that the differentially expressed genes among HIIT, MOD, and MCAO groups were highly associated with signaling pathways involved in inflammatory response, more specifically the I-kappaB kinase/NF-kappaB signaling. Following the outcome, we further investigated the infiltrating immune cells abundant in paretic muscles. The results showed that HIIT modulated macrophage activation by downregulating CD86+ (M1 type) macrophages and upregulating CD163+ (M2 type) macrophages via inhibiting the TLR4/MyD88/NFκB signaling pathway and exerting an anti-inflammatory effect in paretic skeletal muscle. It is expected that these data will provide novel insights into the mechanisms and potential targets underlying muscle wasting in stroke.

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High-Intensity Exercise Training Protects the Brain Against Autoimmune Neuroinflammation: Regulation of Microglial Redox and Pro-inflammatory Functions

Cited by 27 publications

References 58 publications

Exercise training alters autoimmune cell invasion into the brain in autoimmune encephalomyelitis

Exercise training alters autoimmune cell invasion into the brain in autoimmune encephalomyelitis

Glia-Driven Brain Circuit Refinement Is Altered by Early-Life Adversity: Behavioral Outcomes

High-Intensity Interval Training Improves Physical Function, Prevents Muscle Loss, and Modulates Macrophage-Mediated Inflammation in Skeletal Muscle of Cerebral Ischemic Mice

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