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CCR2-deficient mice are protected to sepsis by the disruption of the inflammatory monocytes emigration from the bone
Guilherme Cesar Martelossi Cebinelli1,2, Kalil Alves de Lima1, Fernanda Vargas E Silva Castanheira1
1Center for Research in Inflammatory Diseases (CRID), Department of Pharmacology, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, São Paulo, Brazil.
Abstract:
Sepsis is defined as life-threatening organ dysfunction caused by a dysregulated host response to infection. Inflammatory monocytes are recruited to both the infection site and vital organs during sepsis; however, the mechanisms that orchestrate their migration, as well as the participation of these cells in systemic inflammation and vital organ damage, are still not fully elucidated. In this context, we described that CCR2-deficient mice had diminished migration of inflammatory monocytes from bone marrow to the circulation and subsequently to the site of infection and vital organs during cecal ligation and puncture (CLP)-induced polymicrobial sepsis. The reduction in the migration of inflammatory monocytes to the infection site was accompanied by a significant increase in the number of neutrophils in the same compartment, which seemed to counterbalance the absence of inflammatory monocytes in controlling microbial growth. Indeed, wild-type (WT) and CCR2-deficient mice under CLP presented similar control of infection. However, the CCR2-deficient mice were more resistant to sepsis, which was associated with a decrease in inflammatory mediators and organ damage biomarkers. Furthermore, the systemic adoptive transfer of CCR2-WT or CCR2-deficient inflammatory monocytes into CCR2-deficient mice equally increased the susceptibility to sepsis, demonstrating the deleterious role of these cells in the periphery even when CCR2 is absent. Thus, despite the host-protective role of inflammatory monocytes in controlling infection, our results demonstrated that the mechanism by which CCR2 deficiency shows protection to CLP-induced sepsis is due to a decrease of inflammatory monocytes emigration from bone marrow to the circulation and vital organs, resulting in the reduction of organ damage and systemic cytokine production.
Insights
CCR2 deficiency reduces inflammatory monocyte migration during sepsis, decreasing organ damage and systemic inflammation. This highlights CCR2
Area of Science:
- Immunology
- Pathophysiology
- Microbiology
Background:
- Sepsis involves life-threatening organ dysfunction due to a dysregulated host response to infection.
- Inflammatory monocytes are crucial in sepsis, migrating to infection sites and vital organs, but migration mechanisms and roles in organ damage are unclear.
- CCR2 is a key chemokine receptor involved in monocyte recruitment.
Purpose of the Study:
- To investigate the role of CCR2 in inflammatory monocyte migration during polymicrobial sepsis.
- To elucidate the impact of CCR2-mediated monocyte migration on systemic inflammation and organ damage.
- To determine the net effect of CCR2 deficiency on sepsis outcomes.
Main Methods:
- Utilized cecal ligation and puncture (CLP)-induced polymicrobial sepsis model in CCR2-deficient and wild-type (WT) mice.
- Quantified inflammatory monocyte and neutrophil migration from bone marrow to circulation, infection site, and vital organs.
- Assessed microbial control, inflammatory mediator levels, and organ damage biomarkers.
- Performed systemic adoptive transfer of inflammatory monocytes.
Main Results:
- CCR2-deficient mice exhibited diminished inflammatory monocyte migration to the infection site and vital organs post-CLP.
- Neutrophil numbers increased at the infection site in CCR2-deficient mice, maintaining similar microbial control to WT mice.
- CCR2-deficient mice showed increased resistance to sepsis, with reduced inflammatory mediators and organ damage biomarkers.
- Adoptive transfer of inflammatory monocytes into CCR2-deficient mice increased sepsis susceptibility, confirming their deleterious role.
Conclusions:
- CCR2 deficiency protects against sepsis by reducing inflammatory monocyte emigration from bone marrow to circulation and vital organs.
- Reduced monocyte migration leads to decreased systemic cytokine production and organ damage, despite maintained infection control.
- Inflammatory monocytes play a detrimental role in the systemic inflammatory response during sepsis, even when CCR2 is absent.
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