Differential response to intrahippocampal interleukin-4/interleukin-13 in aged and exercise mice

Abstract

Normal aging is associated with low-grade neuroinflammation that results from age-related priming of microglial cells. Further, aging alters the response to several anti-inflammatory factors, including interleukin (IL)-4 and IL-13. One intervention that has been shown to modulate microglia activation in the aged brain, both basally and following an immune challenge, is exercise. However, whether engaging in exercise can improve responsiveness to anti-inflammatory cytokines is presently unknown. The current study evaluated whether prior exercise training increases sensitivity to anti-inflammatory cytokines that promote the M2 (alternative) microglia phenotype in adult (5-month-old) and aged (23-month-old) C57BL/6J mice. After 8 weeks of exercise or control housing, mice received bilateral hippocampal injections of an IL-4/IL-13 cocktail or vehicle. Twenty-four hours later hippocampal samples were collected and analyzed for expression of genes associated with the M1 (inflammatory) and M2 microglia phenotypes. Results show that IL-4/IL-13 administration increased expression of the M2-associated genes Fizz1, Ym1, Arginase-1 (Arg1), SOCS1, IL-1ra, and CD206. In response to IL-4/IL-13 administration, aged mice showed increased hippocampal expression of the M2-related genes Arg1, SOCS1, Ym1, and CD206 relative to adult mice. Aged mice also showed increased expression of IL-1β relative to adults, which was unaffected by wheel running or IL-4/IL-13. Wheel running was found to have modest effects on expression of Ym1 and Fizz1 in aged and adult mice. Collectively, our findings indicate that aged mice show a differential response to anti-inflammatory cytokines relative to adult mice and that exercise has limited effects on modulating this response.

Young and aged TLR4 deficient mice show sex-dependent enhancements in spatial memory and alterations in interleukin-1 related genes

“…IL-1ra can attenuate IL-1β signaling via competitive binding with the IL-1 type 1 receptor (IL-1R1) (Watkins et al, 1999). Previous reports show that IL-1ra is elevated in serum samples from older adults as well as in the hippocampus of aged mice (Catania et al, 1997;Littlefield and Kohman, 2017). Prior work has shown that aging increases IL-1R1 expression in the hippocampus (Lynch and Lynch, 2002).…”

Dopamine receptor D3 signalling in astrocytes promotes neuroinflammation

“…Accordingly, depending on the integration of different molecular cues, microglial cells might acquire two different phenotypes, including an inflammatory M1 phenotype and an anti-inflammatory M2 phenotype [5]. M1 microglia generates a neurotoxic microenvironment by producing glutamate, TNF-α and reactive oxygen and nitrogen species [6–8], whilst M2 microglia produces anti-inflammatory mediators and neurotrophic factors, such as insulin-like growth factor-1 (IGF-1), brain-derived neurotrophic factor (BDNF), glial-derived neurotrophic factor (GDNF) and found in inflammatory zone 1 (Fizz1) thus inducing a supportive microenvironment for neurons [1, 9–13].…”

CITED2 mediates the cross‐talk between mechanical loading and IL‐4 to promote chondroprotection

“…Of note, moderate exercise is beneficial in disease or aging conditions, such as that represented by the decline in IL‐4 with age, and low‐intensity exercise can produce analgesia mediated by IL‐4 . As age is a risk factor for OA and pain is the major symptom of OA, future studies elucidating the contribution of CITED2‐mediated loading and IL‐4 to pain relief will be of interest.…”