L-Cysteine-Derived H2S Promotes Microglia M2 Polarization via Activation of the AMPK Pathway in Hypoxia-Ischemic Neonatal Mice

Abstract

We have reported previously that L-cysteine-derived hydrogen sulfide (H2S) demonstrates a remarkable neuroprotective effect against hypoxia-ischemic (HI) insult in neonatal animals. Here, we assessed some of the mechanisms of this protection as exerted by L-cysteine. Specifically, we examined the capacity for L-cysteine to stimulate microglial polarization of the M2 phenotype and its modulation of complement expression in response to HI in neonatal mice. L-cysteine treatment suppressed the production of inflammatory cytokines, while dramatically up-regulating levels of anti-inflammatory cytokines in the damaged cortex. This L-cysteine administration promoted the conversion of microglia from an inflammatory M1 to an anti-inflammatory M2 phenotype, an effect which was associated with inhibiting the p38 and/or JNK pro-inflammatory pathways, nuclear factor-κB activation and a decrease in HI-derived levels of the C1q, C3a and C3a complement receptor proteins. Notably, blockade of H2S-production clearly prevented L-cysteine-mediated M2 polarization and complement expression. L-cysteine also inhibited neuronal apoptosis as induced by conditioned media from activated M1 microglia in vitro. We also show that L-cysteine promoted AMP-activated protein kinase (AMPK) activation and the AMPK inhibitor abolished these anti-apoptotic and anti-inflammatory effects of L-cysteine. Taken together, our findings demonstrate that L-cysteine-derived H2S attenuated neuronal apoptosis after HI and suggest that these effects, in part, result from enhancing microglia M2 polarization and modulating complement expression via AMPK activation.

Parthenolide promotes the repair of spinal cord injury by modulating M1/M2 polarization via the NF-κB and STAT 1/3 signaling pathway

“…Our previous studies have shown that after SCI, inflammatory infiltration activates a new type of A1 neurotoxic reactive astrocytes, and inhibiting their activation can promote the recovery of nerve function 72,73 . Considering that type IL-1α, TNF, and C1q, known as typical proinflammatory cytokines produced from M1 phenotype of microglia 40,74 were inducers of A1 astrocytes, and they were secreted by activated microglia under LPS stimulation 35 , which is contributed to microglia M1 polarization 40 , we speculate that the activation of M1 microglia is the key to the activation of A1 astrocytes. This study found that PN could inhibit the activation of A1 astrocytes probably via switching microglia/macrophage M1 phenotype to M2 phenotype, but other mechanisms cannot be ruled out, such as direct restraint of STAT3 activation in astrocytes, which plays a vital role in differentiation of A1 astrocytes 73 .…”

The Role of Host-Generated H2S in Microbial Pathogenesis: New Perspectives on Tuberculosis

“…The studies mentioned above and numerous others have employed inhibitors of CSE and CBS (PAG and AOAA, respectively), L-cysteine and the H 2 S donors NaHS and GYY4137, as well as Cse −/− mice within various macrophage inflammatory models, which clearly established H 2 S as an effector molecule involved in resolution of inflammation by driving macrophages toward an anti-inflammatory M2 phenotype ( Castelblanco et al., 2018 ; Zhou et al., 2019 ; Sunzini et al., 2020 ). Similarly, macrophages infected with Mtb exhibited increased CSE expression and H 2 S levels leading to an anti-inflammatory or M2 macrophage phenotype.…”

Cerebral Immunohistochemical Characterization of the H2S and the Oxytocin Systems in a Porcine Model of Acute Subdural Hematoma

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