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Oncostatin M Receptor Type II Knockout Mitigates Inflammation and Improves Survival from Sepsis in Mice
Saad Y Salim1,2, Nour AlMalki1,2, Kimberly F Macala3,4
1Department of Surgery, University of Alberta, Edmonton, AB T6G 2B7, Canada.
Abstract:
Sepsis remains one of the leading causes of death worldwide. Oncostatin M (OSM), an interleukin (IL)-6 family cytokine, can be found at high levels in septic patients. However, little is known about its role in sepsis. This study aimed to determine if the genetic knockout of OSM receptor (OSMR) type II signaling would improve survival in a murine model of sepsis. Aged (>50 weeks) OSMR type II knockout (KO) mice and wild-type (WT) littermates received an intraperitoneal injection of fecal slurry (FS) or vehicle. The KO mice had better survival 48 h after the injection of FS than the WT mice (p = 0.005). Eighteen hours post-FS injection, the KO mice had reduced peritoneal, serum, and tissue cytokine levels (including IL-1β, IL-6, TNFα, KG/GRO, and IL-10) compared to the WT mice (p < 0.001 for all). Flow cytometry revealed decreased recruitment of CD11b+ F4/80+ Ly6chigh+ macrophages in the peritoneum of KO mice compared to WT mice (34 ± 6 vs. 4 ± 3%, PInt = 0.005). Isolated peritoneal macrophages from aged KO mice had better live E. coli killing capacity than those from WT mice (p < 0.001). Peritoneal lavage revealed greater bacterial counts in KO mice than in WT mice (KO: 305 ± 22 vs. 116 ± 6 CFU (×109)/mL; p < 0.001). In summary, deficiency in OSMR type II receptor signaling provided a survival benefit in the progression of sepsis. This coincided with reduced serum levels of pro-inflammatory (IL-1β, TNFα, and KC/GRO) and anti-inflammatory markers (IL-10), increased bacterial killing ability of macrophages, and reduced macrophage infiltration into to site of infection.
Insights
Targeting the Oncostatin M receptor (OSMR) type II pathway improved sepsis survival in mice. Blocking this signaling reduced inflammation and enhanced macrophage bacterial clearance, offering a potential therapeutic strategy for sepsis.
Area of Science:
- Immunology
- Pathophysiology
- Genetics
Background:
- Sepsis is a leading global cause of mortality.
- Oncostatin M (OSM), an interleukin-6 family cytokine, is elevated in sepsis patients, but its role remains unclear.
- The Oncostatin M receptor (OSMR) type II pathway's involvement in sepsis pathogenesis is not well understood.
Purpose of the Study:
- To investigate the effect of genetically ablating Oncostatin M receptor (OSMR) type II signaling on survival in a murine model of sepsis.
- To elucidate the impact of OSMR type II deficiency on inflammatory responses and macrophage function during sepsis.
Main Methods:
- Aged wild-type (WT) and OSMR type II knockout (KO) mice were subjected to sepsis induction via intraperitoneal fecal slurry (FS) injection.
- Survival rates, serum and peritoneal cytokine levels, macrophage infiltration, and bacterial clearance capacity were assessed.
- Flow cytometry and peritoneal lavage were employed to quantify immune cell populations and bacterial load.
Main Results:
- OSMR type II KO mice exhibited significantly improved survival rates 48 hours post-FS injection compared to WT mice (p = 0.005).
- KO mice showed reduced levels of pro-inflammatory (IL-1β, IL-6, TNFα, KC/GRO) and anti-inflammatory (IL-10) cytokines in serum, peritoneum, and tissues (p < 0.001).
- Deficiency in OSMR type II signaling led to decreased recruitment of specific macrophage populations (CD11b+ F4/80+ Ly6c high+) and enhanced ex vivo bacterial killing capacity by peritoneal macrophages.
Conclusions:
- Genetic deficiency of OSMR type II signaling confers a survival advantage in a murine sepsis model.
- This protective effect is associated with dampened systemic inflammation and improved macrophage-mediated bacterial clearance.
- Targeting the OSMR type II pathway represents a potential therapeutic avenue for sepsis management.
