Csf2 Attenuated Sepsis-Induced Acute Kidney Injury by Promoting Alternative Macrophage Transition

Abstract

Sepsis is a systemic inflammatory state that occurs in response to infection and significantly increases mortality in combination with acute kidney injury (AKI). Macrophages accumulate in the kidney after injury and undergo a transition from a proinflammatory (M1) phenotype to an alternatively activated (M2) phenotype that is required for normal repair. However, the specific signals that regulate the transition from the M1 to M2 phenotype in vivo are unknown. Here, we found an unexpected role of Colony stimulating factor 2 (Csf2) in controlling macrophage transition in vitro and in a mouse model of sepsis induced by cecal ligation and puncture (CLP). We first co-cultured human M1 macrophages with HK-2 cells and characterized cytokine/chemokine profiles via Luminex. Of the cytokines and chemokines that were overexpressed in medium from M1 macrophages cocultured with human kidney-2 (HK-2) cells compared with that from M1 macrophages cultured alone, Csf2 and IL6 showed the greatest increases. Csf2 was exclusively secreted by HK-2 cells but not by M1 macrophages. Furthermore, recombinant human Csf2 protein promoted transition of M1 macrophages to the M2 phenotype in a dose and time-dependent manner. The apoptosis and reactive oxygen species (ROS) release induced by M1 macrophages in HK-2 cells was attenuated after exposure to exogenous Csf2. In addition, the switch from the proinflammatory M1 phenotype to the M2 phenotype occurred via the p-Stat5 pathway, which was activated by Csf2. Importantly, we found that intraperitoneal injection of a Csf2-neutralizing antibody after CLP aggravated kidney injury and suppressed tubular proliferation, subsequently decreasing survival. However, administration of recombinant mouse Csf2 protein could rescue mice with sepsis. Together, our results indicate that Csf2 plays critical roles in regulating macrophage transition via activation of p-STAT5. These data form a foundation upon which new therapeutic strategies can be designed to improve the therapeutic efficacy of cytokine-based treatments for sepsis-induced AKI.

Loganin Attenuates Septic Acute Renal Injury with the Participation of AKT and Nrf2/HO-1 Signaling Pathways

“…1,2 As a terrible generalized hyperinflammatory condition, sepsis patients suffer a variety of tissue injuries and organ dysfunctions involving in lung, kidney, and heart. [3][4][5] Despite many efforts have been made to reduce mortality and improve the cure rate of sepsis worldwide, sepsis remains a terrible disease that seriously threatens the patients. Only 30% septic patients survive according to statistics, besides, at least 6 million patients die from septic infection annually according to the statistics of the World Health Organization (WHO).…”

Uncovering the Gene Regulatory Networks Underlying Macrophage Polarization Through Comparative Analysis of Bulk and Single-Cell Data

“…Canonical M2-associated genes CCL24 and CLEC4A (Makita et al, 2015;Tang et al, 2017) were also induced at 3 hours post-stimuli and reached peak expression around 6 hours ( Figure 1D Lower). M2 also showed higher expression of signaling molecule CSF2 that was recently shown to promote macrophages transition into an M2 phenotype (Li et al, 2020). Therefore, important expression changes leading to terminal polarization of macrophage subtypes were established within the first 6 hours following addition of stimuli.…”

Spi-B Promotes the Recruitment of Tumor-Associated Macrophages via Enhancing CCL4 Expression in Lung Cancer

“…By analyzing microarray data from Spi-B-expressing A549 cells and control cells, we found that the expression of macrophage polarization-and recruitment-related genes, including CSF2, IL6, CCL3, and CCL4, was significantly upregulated by Spi-B. CSF2 is an important survival, proliferation, and differentiation factor for macrophages and neutrophils, and it promotes the infiltration of monocytes and macrophages into injured tissues (24)(25)(26). CSF2 also regulates the switch from the proinflammatory M1 phenotype to the M2 phenotype via the p-Stat5 pathway (24,26,27).…”

“…CSF2 is an important survival, proliferation, and differentiation factor for macrophages and neutrophils, and it promotes the infiltration of monocytes and macrophages into injured tissues (24)(25)(26). CSF2 also regulates the switch from the proinflammatory M1 phenotype to the M2 phenotype via the p-Stat5 pathway (24,26,27). IL6, a proinflammatory cytokine secreted by various cell types, plays several biological roles in different cells (28).…”