Reducing Suppressors of Cytokine Signaling-3 (SOCS3) Expression Promotes M2 Macrophage Polarization and Functional Recovery After Intracerebral Hemorrhage

Abstract

Intracerebral hemorrhage (ICH) is a fatal subtype of stroke, and effective interventions to improve the functional outcomes are still lacking. Suppressor of cytokine signaling 3 (SOCS3) plays critical roles in the inflammatory response by negatively regulating cytokine-Jak–Stat signaling. However, the role of SOCS3 in the regulation of macrophage polarization is highly controversial and the fine regulation exerted by SOCS3 needs further understanding. In this study, rat ICH models were established by infusion of collagenase into the caudate nucleus. To decrease SOCS3 expression into microglia/macrophages in the hemorrhagic lesion area, we injected lentiviral short hairpin RNA (shSOCS3) (Lenti-shSOCS3) into the hematoma cavity at 24 h following ICH. We found that the number of iNOS-positive cells (M1 phenotype) was significantly reduced, whereas arginase-1-positive cells (M2 phenotype) were markedly elevated in animals that received Lenti-shSOCS3 injections compared with those in the Lenti-EGFP and saline groups. The increase in arginase-1-positive cells was associated with a significantly lower pro-inflammatory microenvironment, which included the downregulation of pro-inflammatory cytokines [interleukin (IL)-1β, IL-6, and TNF-α] and concurrent upregulation of anti-inflammatory (IL-10) mediators. In addition, this marked shift toward the M2 phenotype was associated with suppressed NF-κB activation. Furthermore, these changes notably enhanced the neuroprotective effects and functional recovery in Lenti-shSOCS3-injected animals. Our findings indicated that reduction in SOCS3 expression caused a marked bias toward the M2 phenotype and ameliorated the inflammatory microenvironment, which enhanced neuroprotective effects and resulted in notable improvement in functional recovery after ICH.

The use of multiple datasets to identify autophagy-related molecular mechanisms in intracerebral hemorrhage

“…The JAK-STAT pathway has also been associated with ICH progression in rat models (Ji et al, 2020). Our GSEA results also showed that STAT3, which is closely related to mRNA catabolism, is a key gene leading to ICH.…”

“…Previously, researchers found that miRNAs/mRNAs changes in whole-blood samples for patients with ICH were important links with the JAK-STAT pathway ( Cheng et al, 2020 ). The JAK-STAT pathway has also been associated with ICH progression in rat models ( Ji et al, 2020 ). Our GSEA results also showed that STAT3 , which is closely related to mRNA catabolism, is a key gene leading to ICH.…”

Human Adipose Tissue Lysate‐Based Hydrogel for Lasting Immunomodulation to Effectively Improve Spinal Cord Injury Repair

“…[46] SOCS1 improved M2 polarization, while SOCS3 promoted M1 polarization and prevented M2 polarization. [47,48] As shown in Figure 3g, qRT-PCR analysis revealed that HATLH considerably increased the mRNA expression of SOCS1 but decreased the mRNA expression of SOCS3 on M0 macrophages. These data demonstrated that HATLH excellently repolarized M0 to M2, thus facilitating the inhibition of the inflammatory microenvironment after spinal cord damage.…”

Systematic analysis of brain and skull ischemic injury expression profiles reveals associations of the tumor immune microenvironment and cell death with ischemic stroke

“…A recent study has shown that Spp1 , Top2a , and Mki67 played a vital role in the inflammatory response during brain ischemic injury ( 48 , 49 ) and that Ptx3 was an important target in brain ischemic injury and possibly other brain inflammatory disorders ( 50 ). Some other findings indicated that the downregulation of Socs3 in the microglia/macrophages could lead to a marked bias toward the M2 phenotype and ameliorate the inflammation, which could promote neuroprotective effects after stroke ( 51 ). Therefore, this suggests that ischemic injury-associated genes play different roles in different tumor environments.…”