Early‐life thermal stress mediates long‐term alterations in hypothalamic microglia

Abstract

Stressful environmental events in early life have long-lasting consequences on later stress responses. We previously showed that heat conditioning of 3-day-old chicks during the critical period of heat-response development leads to heat vulnerability later in life. Here we assessed the role of early-life heat stress on the inflammatory response in the chick anterior hypothalamus (AH), focusing on hypothalamic microglia. We identified the microglial cell population in the chick AH using anti-KUL01 and anti-CD45 antibodies. Specific microglial features were also confirmed by expression of their signature genes. Under normal environmental conditions, hypothalamic microglia isolated from lipopolysaccharide (LPS)-injected chicks displayed a classical activated proinflammatory profile accompanied by a decreased homeostatic signature, demonstrating similarity of immune response with mammalian microglial cells. In accordance with our previous observations, conditioning of 3-dayold chicks under high ambient temperature decreased the number of newborn cells in the AH, among them microglial precursors. Although heat exposure did not affect microglial cell viability, it had a long-term impact on LPS-induced inflammatory response. Exposure to harsh heat led to heat vulnerability, and attenuated recruitment of peripheral monocytes and T cells into the AH following LPS challenge. Moreover, heat conditioning altered microglial reactivity, manifested as suppressed microglial activation in response to LPS. Innate immune memory developed by heat conditioning might underlie suppression of the microglial response to LPS challenge.We describe alterations in genome-wide CpG methylation profile of hypothalamic microglia, demonstrating probable epigenetic involvement in the reprogramming of microglial function, leading to heat-induced inflammatory cross-tolerance.

BHBA attenuates endoplasmic reticulum stress‐dependent neuroinflammation via the gut–brain axis in a mouse model of heat stress

“… 31 In an early study of HS on the inflammatory response in the anterior hypothalamus (AH) of chicks, it was found that HS altered the reactivity of hypothalamic microglia as manifested by suppression of microglia in response to LPS stimulation. 57 Another important issue during the assessment of microglia status, in addition to morphological approaches, is the reliance on Iba‐1 immunoreactivity to report their activation status. 58 Interestingly, our study found a considerable increase in microglial cell overactivation and proliferation in the HS animal model, which was alleviated by BHBA therapy.…”

“…found that HS can induce excessive activation of microglia and astrocytes during the generation of neuroinflammation 31 . In an early study of HS on the inflammatory response in the anterior hypothalamus (AH) of chicks, it was found that HS altered the reactivity of hypothalamic microglia as manifested by suppression of microglia in response to LPS stimulation 57 . Another important issue during the assessment of microglia status, in addition to morphological approaches, is the reliance on Iba‐1 immunoreactivity to report their activation status 58 .…”

Innate Immune Tolerance in Microglia Does Not Impact on Central Nervous System Prion Disease

“…As a consequence, consecutive LPS treatment caused long-term changes in the microglia that months later were sufficient to alter the development of pathology in an experimental mouse model of stroke (focal cortical ischemia) and impede the subsequent development of neuropathology in a spontaneous transgenic mouse model of Alzheimer’s disease-like pathology ( Wendeln et al, 2018 ). Other studies have shown how similar systemic stimuli ( Zhou et al, 2020 ), a high-fat diet ( Vargas-Rodríguez et al, 2022 ), and early life thermal stress ( Ben-Nun et al, 2022 ) can cause long-term changes in microglial responses that can impede their responses to subsequent pro-inflammatory stimuli. The immune tolerance induced in the microglia to these repeated stimuli may be a neuroprotective response to protect the CNS from repetitive or subsequent pro-inflammatory insults ( Lajqi et al, 2020 ; Zhou et al, 2020 ).…”